Kras g12c inhibitors

ABSTRACT

The present invention relates to compounds that inhibit KRas G12C. In particular, the present invention relates to compounds that irreversibly inhibit the activity of KRas G12C, pharmaceutical compositions comprising the compounds and methods of use therefor.

FIELD OF THE INVENTION

The present invention relates to compounds that inhibit KRas G12C. Inparticular, the present invention relates to compounds that irreversiblyinhibit the activity of KRas G12C, pharmaceutical compositionscomprising the compounds and methods of use therefor.

BACKGROUND OF THE INVENTION

Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (“KRas”) is a small GTPaseand a member of the Ras family of oncogenes. KRas serves a molecularswitch cycling between inactive (GDP-bound) and active (GTP-bound)states to transduce upstream cellular signals received from multipletyrosine kinases to downstream effectors to regulate a wide variety ofprocesses, including cellular proliferation (e.g., see Alamgeer et al.,(2013) Current Opin Pharmcol. 13:394-401).

The role of activated KRas in malignancy was observed over thirty yearsago (e.g., see Santos et al., (1984) Science 223:661-664). Aberrantexpression of KRas accounts for up to 20% of all cancers and oncogenicKRas mutations that stabilize GTP binding and lead to constitutiveactivation of KRas and downstream signaling have been reported in 25-30%of lung adenocarcinomas. (e.g., see Samatar and Poulikakos (2014) NatRev Drug Disc 13(12): 928-942 doi: 10.1038/nrd428). Single nucleotidesubstitutions that result in missense mutations at codons 12 and 13 ofthe KRas primary amino acid sequence comprise approximately 40% of theseKRas driver mutations in lung adenocarcinoma, with a G12C transversionbeing the most common activating mutation (e.g., see Dogan et al.,(2012) Clin Cancer Res. 18(22)-6169-6177, published online 2012 Sep. 26.doi: 10.1158/1078-0432 CCR-11-3265).

The well-known role of KRAs in malignancy and the discovery of thesefrequent mutations in KRas in various tumor types made KRas a highlyattractable target of the pharmaceutical industry for cancer therapyNotwithstanding thirty years of large scale discovery efforts to developinhibitors of KRas for treating cancer, no KRas inhibitor hasdemonstrated sufficient safety and/or efficacy to obtain regulatoryapproval (e.g., see McCormick (2015) Clin Cancer Res. 21 (8):1797-1801).

Despite many failed efforts to target KRas, compounds that inhibit KRasactivity are still highly desirable and under investigation, includingthose that disrupt effectors such as guanine nucleotide exchange factors(e.g., see Sun et al., (2012) Agnew Chem Int Ed Engl. 51(25):6140-6143doi: 10.1002/anie201201358) as well target KRas G12C (e.g., see Ostremet al., (2013) Nature 503:548-551). Clearly there remains a continuedinterest and effort to develop inhibitors of KRas, particularlyinhibitors of activating KRas mutants, including KRas G12C.

Thus, there is a need to develop new KRas G12C inhibitors thatdemonstrate sufficient efficacy, stability and/or safety for treatingKRas G12C-mediated cancer. The compounds and compositions of the presentinvention advantageously overcome one or more of the previousshortcomings by providing selective KRas G12C inhibitors.

SUMMARY OF THE INVENTION

In one aspect of the invention, compounds are provided that inhibit KRasG12C activity. In certain embodiments, the compounds are represented byformula (I):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   X is a 4-12 membered saturated or partially saturated        monocyclic, bridged or spirocyclic ring, wherein the saturated        or partially saturated monocyclic ring is optionally substituted        with one or more R⁸;    -   Y is a bond, O, S or NR⁵;    -   R¹ is —C(O)C(R^(A))        C(R^(B))_(p) or —SO₂C(R^(A))        C(R^(B))_(p);    -   R² is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl,        alkylaminylalkyl, dialkylaminylalkyl, —Z—NR⁵R¹⁰, heterocyclyl,        heterocyclylalkyl, aryl, heteroaryl, or heteroarylalkyl, wherein        each of the Z, heterocyclyl, heterocyclylalkyl, aryl,        heteroaryl, and heteroarylalkyl may be optionally substituted        with one or more R⁹;    -   Z is C1-C4 alkylene;    -   each R³ is independently C1-C3 alkyl, oxo, or haloalkyl;    -   L is a bond, —C(O)—, or C1-C3 alkylene;    -   R⁴ is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl or        heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl,        aralkyl and heteroaryl may be optionally substituted with one or        more R⁶ or R⁷;    -   each R⁵ is independently hydrogen or C1-C3 alkyl;    -   R⁶ is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or        heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl,        or heteroaryl may be optionally substituted with one or more R⁷;    -   each R⁷ is independently halogen, hydroxyl, C1-C6 alkyl,        cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl,        hydroxyalkyl or Q-haloalkyl, wherein Q is O or S;    -   R⁸ is oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano,        —C(O)OR⁵, —C(O)N(R⁵)₂, —N(R⁵)₂, wherein the C1-C3 alkyl may be        optionally substituted with cyano, halogen, —OR⁵, —N(R⁵)₂, or        heteroaryl    -   each R⁹ is independently hydrogen, oxo, acyl, hydroxyl,        hydroxyalkyl, cyano, halogen, C1-C6 alkyl, aralkyl, haloalkyl,        heteroalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl,        alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl,        wherein the C1-C6 alkyl may be optionally substituted with        cycloalkyl;    -   each R¹⁰ is independently hydrogen, acyl, C1-C3 alkyl,        heteroalkyl or hydroxyalkyl;    -   R^(A) is absent, hydrogen, or C1-C3 alkyl;    -   each R^(B) is independently hydrogen, C1-C3 alkyl,        alkylaminylalkyl, dialkylaminylalkyl or heterocyclylalkyl;    -   m is zero or an integer between 1 and 2;    -   p is one or two; and wherein,    -   when        is a triple bond then R^(A) is absent, R^(B) is present and p        equals one,    -   or when        is a double bond then R^(A) is present, R^(B) is present and p        equals two, or R^(A), R^(B) and the carbon atoms to which they        are attached form a 5-8 membered partially saturated cycloalkyl        optionally substituted with one or more R⁷.

Also included are compounds of Formula I having the Formula I-A:

-   -   wherein R¹, R³, R⁴, R⁵, R¹⁰, L and m are as defined for Formula        I, R¹¹ is hydrogen, C1-C3 alkyl or hydroxyalkyl, and the        piperazinyl ring is optionally substituted with R⁸ wherein R⁸ is        as defined for Formula I.

Also included are compounds of Formula I having the Formula I-B:

-   -   where R¹, R³, R⁴, L and m are as defined for Formula I, R² is        heterocyclylalkyl optionally substituted with one or more R⁹        where R⁹ is as defined for Formula I, and the piperazinyl ring        is optionally substituted with R⁸, where R⁸ is as defined for        Formula I.

In certain embodiments, the compounds are represented by Formula (II):

-   -   or a pharmaceutically acceptable salt thereof:    -   wherein:    -   X is a 4-12 membered saturated or partially saturated        monocyclic, bridged or spirocyclic ring, wherein the saturated        or partially saturated monocyclic ring is optionally substituted        with one or more R⁸;    -   Y is a bond, O, S or NR⁵;    -   R¹ is —C(O)C(R^(A))        C(R^(B))_(p) or —SO₂C(R^(A))        C(R^(B))_(p);    -   R² is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl,        alkylaminylalkyl, dialkylaminylalkyl, —Z—NR⁵R¹⁰, heterocyclyl,        heterocyclylalkyl, aryl, heteroaryl, or heteroarylalkyl, wherein        each of the Z, heterocyclyl, heterocyclylalkyl, aryl,        heteroaryl, and heteroarylalkyl may be optionally substituted        with one or more R⁹;    -   each Z is C1-C4 alkylene;    -   each R³ is independently C1-C3 alkyl, oxo, haloalkyl, hydroxyl        or halogen;    -   L is a bond, —C(O)—, or C1-C3 alkylene;    -   R⁴ is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl or        heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl,        aralkyl and heteroaryl may be optionally substituted with one or        more R⁶, R⁷ or R⁸;    -   each R⁵ is independently hydrogen or C1-C3 alkyl;    -   R⁶ is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or        heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl,        or heteroaryl may be optionally substituted with one or more R⁷;    -   each R⁷ is independently halogen, hydroxyl, C1-C6 alkyl,        cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl,        hydroxyalkyl or Q-haloalkyl, wherein Q is O or S;    -   R⁸ is oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano,        —C(O)OR⁵, —C(O)N(R⁵)₂, —N(R⁵)₂, wherein the C1-C3 alkyl may be        optionally substituted with cyano, halogen, —OR⁵, —N(R⁵)₂, or        heteroaryl;    -   each R⁹ is independently hydrogen, oxo, acyl, hydroxyl,        hydroxyalkyl, cyano, halogen, C1-C6 alkyl, aralkyl, haloalkyl,        heteroalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl,        alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl,        wherein the C1-C6 alkyl may be optionally substituted with        cycloalkyl;    -   each R¹⁰ is independently hydrogen, acyl, C1-C3 alkyl,        heteroalkyl or hydroxyalkyl;    -   R¹¹ is haloalkyl;    -   R^(A) is absent, hydrogen, deuterium, cyano, halogen, C1-C-3        alkyl, haloalkyl, heteroalkyl, —C(O)N(R⁵)₂, or hydroxyalkyl;    -   each R^(B) is independently hydrogen, deuterium, cyano, C1-C3        alkyl, hydroxyalkyl, heteroalkyl, C1-C3 alkoxy, halogen,        haloalkyl, —ZNR⁵R¹¹, —C(O)N(R⁵)₂, —NHC(O)C1-C3 alkyl,        —CH₂NHC(O)C1-C3 alkyl, heteroaryl, heteroarylalkyl,        dialkylaminylalkyl, or heterocyclylalkyl wherein the        heterocyclyl portion is substituted with one or more        substituents independently selected from halogen, hydroxyl,        alkoxy and C1-C3 alkyl, wherein the heteroaryl or the heteroaryl        portion of the heteroarylalkyl is optionally substituted with        one or more R⁷;    -   or when        is a double bond and p is two, one R^(B) is hydrogen and R^(A)        and one R^(B) and the carbon atoms to which they are attached        form a 5-8 membered partially saturated cycloalkyl substituted        with oxo;    -   m is zero or an integer between 1 and 2;    -   p is one or two; and wherein,    -   when        is a triple bond then R^(A) is absent, p equals one and R^(B) is        hydroxyalkyl,    -   or when        is a double bond then R^(A) is present, R^(B) is present and p        equals two, wherein when R^(A) is hydrogen or C1-C3 alkyl at        least one R^(B) is deuterium, cyano, halogen, haloalkyl,        hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl,        —ZNR⁵R¹¹, —C(O)N(R⁵)₂, —NHC(O)C1-C3 alkyl, —CH₂NHC(O)C1-C3 alkyl        or heterocyclylalkyl, wherein the heterocyclyl portion is        substituted with one or more substituents independently selected        from halogen, hydroxyl, alkoxy or C1-C3 alkyl; or when each        R^(B) is hydrogen, then R^(A) is deuterium, cyano, halogen,        haloalkyl, —C(O)N(R⁵)₂, hydroxyalkyl or heteroalkyl.

Also included are compounds of Formula II having the Formula II-A:

-   -   wherein R¹, R³, R⁴, R⁵, R¹⁰, L and m are as defined for Formula        II, R¹¹ is hydrogen, C1-C3 alkyl or hydroxyalkyl, and the        piperazinyl ring is optionally substituted with R⁸ wherein R⁸ is        as defined for Formula II.

Also included are compounds of Formula II having the Formula II-B:

-   -   where R¹, R³, R⁴, R⁸, L and m are as defined for Formula II, R²        is heterocyclylalkyl optionally substituted with one or more R⁹,        and the piperazinyl ring is optionally substituted with R⁸,        where R⁸ is as defined for Formula II.

In another aspect of the invention, pharmaceutical compositions areprovided comprising a therapeutically effective amount of a compound ofthe present invention or a pharmaceutically acceptable salt thereof anda pharmaceutically acceptable excipient.

In yet another aspect of the invention, methods for inhibiting KRas G12Cactivity in a in a cell, comprising contacting the cell with a compoundof Formula I, Formula I-A, Formula I-B, Formula II, Formula II-A orFormula II-B. In one embodiment, the contacting is in vitro. In oneembodiment, the contacting is in vivo.

Also provided herein is a method of inhibiting cell proliferation, invitro or in vivo, the method comprising contacting a cell with aneffective amount of a compound of Formula I, Formula I-A, Formula I-B,Formula II, Formula II-A or Formula II-B, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition thereof asdefined herein.

Also provided are methods for treating cancer in a patient comprisingadministering a therapeutically effective amount of a compound orpharmaceutical composition of the present invention or apharmaceutically acceptable salt thereof to a patient in need thereof.

Also provided herein is a method of treating a KRas G12C-associateddisease or disorder in a patient in need of such treatment, the methodcomprising administering to the patient a therapeutically effectiveamount of a compound of Formula I, Formula I-A, Formula I-B, Formula II,Formula II-A or Formula II-B, or a pharmaceutically acceptable salt orsolvate thereof, or a pharmaceutical composition thereof as definedherein.

Also provided herein is a compound of Formula I, Formula I-A, FormulaI-B, Formula II, Formula II-A or Formula II-B, or a pharmaceuticallyacceptable salt or solvate thereof, or a pharmaceutical compositionthereof as defined herein for use in therapy.

Also provided herein is a compound of Formula I, Formula I-A, FormulaI-B, Formula II, Formula II-A or Formula II-B, or a pharmaceuticallyacceptable salt or solvate thereof or a pharmaceutical compositionthereof as defined herein for use in the treatment of cancer.

Also provided herein is a compound of Formula I, Formula I-A, FormulaI-B, Formula II, Formula II-A or Formula II-B, or a pharmaceuticallyacceptable salt or solvate thereof for use in the inhibition of KRasG12C.

Also provided herein is a compound of Formula I, Formula I-A, FormulaI-B, Formula II, Formula II-A or Formula II-B, or a pharmaceuticallyacceptable salt or solvate thereof or a pharmaceutical compositionthereof as defined herein, for use in the treatment of a KRasG12C-associated disease or disorder.

Also provided herein is the use of a compound of Formula I, Formula I-A,Formula I-B, Formula II, Formula II-A or Formula II-B, or apharmaceutically acceptable salt or solvate thereof, as defined hereinin the manufacture of a medicament for the treatment of cancer.

Also provided herein is a use of a compound of Formula I, Formula I-A,Formula I-B, Formula II, Formula II-A or Formula II-B, or apharmaceutically acceptable salt or solvate thereof, as defined hereinin the manufacture of a medicament for the inhibition of activity ofKRas G12C.

Also provided herein is the use of a compound of Formula I, Formula I-A,Formula I-B, Formula II, Formula II-A or Formula II-B, or apharmaceutically acceptable salt or solvate thereof, as defined herein,in the manufacture of a medicament for the treatment of a KRasG12C-associated disease or disorder.

Also provided herein is a method for treating cancer in a patient inneed thereof, the method comprising (a) determining that the cancer isassociated with a KRas G12C mutation (e.g., a KRas G12C-associatedcancer); and (b) administering to the patient a therapeuticallyeffective amount of a compound of Formula I, Formula I-A, Formula I-B,Formula II, Formula II-A or Formula II-B, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition thereof.

Also provided herein is a process for preparing a compound of Formula I,Formula I-A, Formula I-B, Formula II, Formula II-A or Formula II-B, or apharmaceutically acceptable salt or solvate thereof.

Also provided herein is a compound of Formula I, Formula I-A, FormulaI-B, Formula II, Formula II-A or Formula II-B, or a pharmaceuticallyacceptable salt thereof obtained by a process of preparing the compoundas defined herein.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to inhibitors of KRas G12C. In particular,the present invention relates to compounds that irreversibly inhibit theactivity of KRas G12C, pharmaceutical compositions comprising atherapeutically effective amount of the compounds and methods of usetherefor.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this invention belongs. All patents, patent applications,and publications referred to herein are incorporated by reference.

As used herein, “KRas G12C” refers to a mutant form of a mammalian KRasprotein that contains an amino acid substitution of a cysteine for aglycine at amino acid position 12. The assignment of amino acid codonand residue positions for human KRas is based on the amino acid sequenceidentified by UniProtKB/Swiss-Prot P01116: Variant p.Gly12Cys.

As used herein, a “KRas G12C inhibitor” refers to compounds of thepresent invention that are represented by formulae (I) as describedherein. These compounds are capable of negatively modulating orinhibiting all or a portion of the enzymatic activity of KRas G12C. TheKRas G12C inhibitors of the present invention interact with andirreversibly bind to KRas G12C by forming a covalent adduct with thesulfhydryl side chain of the cysteine residue at position 12 resultingin the inhibition of the enzymatic activity of KRas G12C.

A “KRas G12C-associated disease or disorder” as used herein refers todiseases or disorders associated with or mediated by or having a KRasG12C mutation. A non-limiting example of a KRas G12C-associated diseaseor disorder is a KRas G12C-associated cancer.

As used herein, the term “subject,” “individual,” or “patient,” usedinterchangeably, refers to any animal, including mammals such as mice,rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses,primates, and humans. In some embodiments, the patient is a human. Insome embodiments, the subject has experienced and/or exhibited at leastone symptom of the disease or disorder to be treated and/or prevented.In some embodiments, the subject has been identified or diagnosed ashaving a cancer having a KRas G12C mutation (e.g., as determined using aregulatory agency-approved, e.g., FDA-approved, assay or kit). In someembodiments, the subject has a tumor that is positive for a KRas G12Cmutation (e.g., as determined using a regulatory agency-approved assayor kit). The subject can be a subject with a tumor(s) that is positivefor a KRas G12C mutation (e.g., identified as positive using aregulatory agency-approved, e.g., FDA-approved, assay or kit). Thesubject can be a subject whose tumors have a KRas G12C mutation (e.g.,where the tumor is identified as such using a regulatoryagency-approved, e.g., FDA-approved, kit or assay). In some embodiments,the subject is suspected of having a KRas G12C gene-associated cancer.In some embodiments, the subject has a clinical record indicating thatthe subject has a tumor that has a KRas G12C mutation (and optionallythe clinical record indicates that the subject should be treated withany of the compositions provided herein).

In some embodiments of any of the methods or uses described herein, anassay is used to determine whether the patient has KRas G12C mutationusing a sample (e.g., a biological sample or a biopsy sample (e.g., aparaffin-embedded biopsy sample) from a patient (e.g., a patientsuspected of having a KRas G12C-associated cancer, a patient having oneor more symptoms of a KRas G12C-associated cancer, and/or a patient thathas an increased risk of developing a KRas G12C-associated cancer) caninclude, for example, next generation sequencing, immunohistochemistry,fluorescence microscopy, break apart FISH analysis, Southern blotting.Western blotting, FACS analysis, Northern blotting, and PCR-basedamplification (e.g., RT-PCR and quantitative real-time RT-PCR). As iswell-known in the art, the assays are typically performed, e.g., with atleast one labelled nucleic acid probe or at least one labelled antibodyor antigen-binding fragment thereof.

The term “regulatory agency” is a country's agency for the approval ofthe medical use of pharmaceutical agents with the country. For example,a non-limiting example of a regulatory agency is the U.S. Food and DrugAdministration (FDA).

The term “amino” refers to —NH₂;

The term “acyl” refers to —C(O)CH₃.

The term “alkyl” as employed herein refers to straight and branchedchain aliphatic groups having from 1 to 12 carbon atoms, 1-8 carbonatoms 1-6 carbon atoms, or 1-3 carbon atoms which is optionallysubstituted with one, two or three substituents. Examples of alkylgroups include, without limitation, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

The term “haloalkyl” refers to an alkyl chain in which one or morehydrogen has been replaced by a halogen. Examples of haloalkyls aretrifluoromethyl, difluoromethyl and fluoromethyl.

The term “haloalkyloxy” refers to —O-haloalkyl.

An “alkylene,” group is an alkyl group, as defined hereinabove, that ispositioned between and serves to connect two other chemical groups.Exemplary alkylene groups include, without limitation, methylene,ethylene, propylene, and butylene.

The term “alkoxy” refers to —OC1-C6 alkyl.

The term “cycloalkyl” as employed herein includes saturated andpartially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons,for example 3 to 8 carbons, and as a further example 3 to 6 carbons,wherein the cycloalkyl group additionally is optionally substitutedExamples of cycloalkyl groups include, without limitation, cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,cycloheptyl, and cyclooctyl.

The term “heteroalkyl” refers to an alkyl group, as defined hereinabove,wherein one or more carbon atoms in the chain are replaced by aheteroatom selected from the group consisting of O, S, and N.

As used herein, the term “hydroxyalkyl” refers to -alkyl-OH.

The term “dihydroxyalkyl” refers to an alkyl group as defined hereinwherein two carbon atoms are each substituted with a hydroxyl group.

The term “alkylaminyl” refers to —NR^(x)-alkyl, wherein R^(x) ishydrogen. In one embodiment, R^(x) is hydrogen.

The term “dialkylaminyl” refers to —N(R^(y))₂, wherein each R^(y) isC1-C3 alkyl.

The term “alkylaminylalkyl” refers to -alkyl-NR^(x)-alkyl, wherein R^(x)is hydrogen. In one embodiment, R^(x) is hydrogen.

The term “dialkylaminylalkyl” refers to -alkyl-N(R^(y))₂, wherein eachR^(y) is C1-C4 alkyl, wherein the alkyl of the -alkyl-N(R^(y))₂ may beoptionally substituted with hydroxy or hydroxyalkyl.

An “aryl” group is a C₆-C₁₄ aromatic moiety comprising one to threearomatic rings, which is optionally substituted. As one embodiment, thearyl group is a C₆-C₁₀ aryl group. Examples of aryl groups include,without limitation, phenyl, naphthyl, anthracenyl, fluorenyl, anddihydrobenzofuranyl.

An “aralkyl” or “arylalkyl” group comprises an aryl group covalentlylinked to an alkyl group, either of which may independently beoptionally substituted or unsubstituted. An example of an aralkyl groupis (C₁-C₆)alkyl(C₆-C₁₀)aryl, including, without limitation, benzyl,phenethyl, and naphthylmethyl. An example of a substituted aralkyl iswherein the alkyl group is substituted with hydroxyalkyl.

A “heterocyclyl” or “heterocyclic” group is a ring structure having fromabout 3 to about 12 atoms, for example 4 to 8 atoms, wherein one or moreatoms are selected from the group consisting of N, O, and S, theremainder of the ring atoms being carbon. The heterocyclyl may be amonocyclic, a bicyclic, a spirocyclic or a bridged ring system. Theheterocyclic group is optionally substituted with R⁷ on carbon ornitrogen at one or more positions, wherein R⁷ is as defined for FormulaI. The heterocyclic group is also independently optionally substitutedon nitrogen with alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl,arylcarbonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, or onsulfur with oxo or lower alkyl. Examples of heterocyclic groups include,without limitation, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl,tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl,piperazinyl, imidazolidinyl, thiazolidinyl, dithianyl, trithianyl,dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl,piperidonyl, 4-piperidinonyl, thiomorpholinyl, thiomorpholinyl 1,1dioxide, morpholinyl, oxazepanyl, azabicyclohexanes, azabicycloheptanesand oxa azabiocycloheptanes. Specifically excluded from the scope ofthis term are compounds having adjacent annular O and/or S atoms.

The term “heterocyclylalkyl” refers to a heterocyclyl group as definedherein linked to the remaining portion of the molecule via an alkyllinker, wherein the alkyl linker of the heterocyclylalkyl may beoptionally substituted with hydroxy or hydroxyalkyl.

As used herein, the term “heteroaryl” refers to groups having 5 to 14ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 πelectrons shared in a cyclic array; and having, in addition to carbonatoms, from one to three heteroatoms per ring selected from the groupconsisting of N, O, and S. Examples of heteroaryl groups includeacridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl,cinnolinyl, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H-indazolyl,indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl,pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole,pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl,2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,quinoxalinyl, quinuclidinyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, andxanthenyl.

A “heteroarylalkyl” group comprises a heteroaryl group covalently linkedto an alkyl group, wherein the radical is on the alkyl group, either ofwhich is independently optionally substituted or unsubstituted. Examplesof heteroarylalkyl groups include a heteroaryl group having 5, 6, 9, or10 ring atoms bonded to a C1-C6 alkyl group. Examples of heteroaralkylgroups include pyridylmethyl, pyridylethyl, pyrrolylmethyl,pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl,thiazolylethyl, benzimidazolylmethyl, benzimidazolylethylquinazolinylmethyl, quinolinylmethyl, quinolinylethyl,benzofuranylmethyl, indolinylethyl isoquinolinylmethyl, isoinodylmethyl,cinnolinylmethyl, and benzothiophenylethyl. Specifically excluded fromthe scope of this term are compounds having adjacent annular O and/or Satoms.

As used herein, “an effective amount” of a compound is an amount that issufficient to negatively modulate or inhibit the activity of KRas G12C.Such amount may be administered as a single dosage or may beadministered according to a regimen, whereby it is effective.

As used herein, a “therapeutically effective amount” of a compound is anamount that is sufficient to ameliorate, or in some manner reduce asymptom or stop or reverse progression of a condition, or negativelymodulate or inhibit the activity of KRas G12C. Such amount may beadministered as a single dosage or may be administered according to aregimen, whereby it is effective.

As used herein, treatment means any manner in which the symptoms orpathology of a condition, disorder or disease are ameliorated orotherwise beneficially altered. Treatment also encompasses anypharmaceutical use of the compositions herein.

As used herein, amelioration of the symptoms of a particular disorder byadministration of a particular pharmaceutical composition refers to anylessening, whether permanent or temporary, lasting or transient that canbe attributed to or associated with administration of the composition.

Compounds

In one aspect of the invention, compounds are provided represented byformula (I):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   X is a 4-12 membered saturated or partially saturated        monocyclic, bridged or spirocyclic ring, wherein the saturated        or partially saturated monocyclic ring is optionally substituted        with one or more R⁸;    -   Y is a bond, O, S or NR⁵;    -   R¹ is —C(O)C(R^(A))        C(R^(B))_(p) or —SO₂C(R^(A))        C(R^(B))_(p);    -   R² is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl,        alkylaminylalkyl, dialkylaminylalkyl, —Z—NR⁵R¹⁰, heterocyclyl,        heterocyclylalkyl, aryl, heteroaryl, or heteroarylalkyl, wherein        each of the Z, heterocyclyl, heterocyclylalkyl, aryl,        heteroaryl, and heteroarylalkyl may be optionally substituted        with one or more R⁹;    -   Z is C1-C4 alkylene;    -   each R³ is independently C1-C3 alkyl, oxo, or haloalkyl;    -   L is a bond, —C(O)—, or C1-C3 alkylene;    -   R⁴ is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl or        heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl,        aralkyl and heteroaryl may be optionally substituted with one or        more R⁶ or R⁷;    -   each R⁵ is independently hydrogen or C1-C3 alkyl;    -   R⁶ is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or        heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl,        or heteroaryl may be optionally substituted with one or more R⁷;    -   each R⁷ is independently halogen, hydroxyl, C1-C6 alkyl,        cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl,        hydroxyalkyl or Q-haloalkyl, wherein Q is O or S;    -   R⁸ is oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano,        —C(O)OR⁵, —C(O)N(R⁵)₂, —N(R⁵)₂, wherein the C1-C3 alkyl may be        optionally substituted with cyano, halogen, —OR⁵, —N(R⁵)₂, or        heteroaryl;    -   each R⁹ is independently hydrogen, oxo, acyl, hydroxyl,        hydroxyalkyl, cyano, halogen, C1-C6 alkyl, aralkyl, haloalkyl,        heteroalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl,        alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl,        wherein the C1-C6 alkyl may be optionally substituted with        cycloalkyl;    -   each R¹⁰ is independently hydrogen, acyl, C1-C3 alkyl,        heteroalkyl or hydroxyalkyl;    -   R^(A) is absent, hydrogen, or C1-C3 alkyl;    -   each R^(B) is independently hydrogen, C1-C3 alkyl,        alkylaminylalkyl, dialkylaminylalkyl or heterocyclylalkyl;    -   m is zero or an integer between 1 and 2;    -   p is one or two; and wherein,    -   when        is a triple bond then R^(A) is absent, R^(B) is present and p        equals one;    -   or when        is a double bond then R^(A) is present, R^(B) is present and p        equals two, or R^(A), R^(B) and the carbon atoms to which they        are attached form a 5-8 membered partially saturated cycloalkyl        optionally substituted with one or more R⁷.

In certain embodiments, R¹—X is:

-   -   wherein R¹ is are defined for Formula I and the piperazinyl ring        is optionally substituted with R⁸, where R⁸ is as defined for        Formula I. In certain embodiments, R⁸ is C1-C3 alkyl wherein the        alkyl is optionally substituted with cyano or OR⁵, or        —C(O)N(R⁵)₂, wherein each R⁵ is independently hydrogen or C1-C3        alkyl.

In particular embodiments, R¹ is —C(O)C(R^(A))

C(R^(B))_(p) where R^(A), R^(B) and p are as defined for Formula I. Inone embodiment, R¹ is —C(O)C(R^(A))

C(R^(B))_(p), wherein

is a triple bond and R^(A) is absent, p is one and R^(B) is C1-C3 alkyl.In one embodiment, R¹ is —C(O)C(R^(A))

C(R^(B))_(p), wherein

is a double bond and R^(A) is hydrogen or C1-C3alkyl, p is two and eachR^(B) is independently hydrogen, C1-C3alkyl, dialkylaminylalkyl orheterocyclylalkyl. In one embodiment, R¹ is —C(O)C(R^(A))═C(R^(B))_(p),wherein R^(A) is hydrogen or C1-C3alkyl, p is two, one of said R^(B) ishydrogen, C1-C3alkyl, dialkylaminylalkyl or heterocyclylalkyl and theother R^(B) is hydrogen or C1-C3alkyl. In one embodiment, R¹ is—C(O)CH═CH₂.

In one embodiment, Y is O or NR⁵ and R² is selected from the groupconsisting of alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl,dialkylaminylalkyl, heterocyclyl, heterocyclylalkyl, and heteroaryl. Inone embodiment, Y is O and R² is hydroxyalkyl, dihydroxyalkyl,alkylaminylalkyl, or dialkylaminylalkyl, wherein the alkylaminylalkyl ordialkylaminylalkyl is optionally substituted with one or more R⁹. In oneembodiment, the optionally substituted alkylaminylalkyl ordialkylaminylalkyl is independently selected frommethylaminylpropan-2-yl, dimethylaminylethyl, methylethylaminylethyl,dimethylaminylpropanyl, dimethylaminylpropan-2-yl,dimethylaminylbutanyl, dimethylaminylbutan-2-yl,2-dimethylaminylpropanol, or diethylaminylethyl. In one embodiment, Y isO or NR⁵ and R² is heterocyclyl or heterocyclylalkyl optionallysubstituted with one or more R⁹. Nonlimiting examples of one or more R⁹when R² is heterocyclyl or heterocyclylalkyl include C1-C3 alkyl, acyl,oxo, cyano, alkoxy, cycloalkyl, cycloalkylmethyl, halogen, and hydroxyl.Nonlimiting examples of R² heterocyclyls optionally substituted with oneor more R⁹ include azetidinyl. C1-C3alkyl-substituted azetidinyl (e.g.,methylazetidinyl), halo-substituted azetidinyl (e.g.,difluoroazetidinyl), tetrahydropyran, pyrrolidinyl, C1-C3alkyl-substituted pyrrolidinyl (e.g., methylpyrrolidinyl,dimethylpyrrolidinyl, and isopropylpyrrolidinyl),cycloalkylalkylpyrrolidinyl, hydroxypyrrolindinyl, halo-substitutedpyrrolidinyl (e.g., fluoropyrrolidinyl and difluoropyrrolidinyl),methoxyethylpyrrolidinyl, (N-methyl)methoxypyrrolidinyl, piperazinyl,dimethylaminylpyrrolidinyl, morpholinyl, methylmorpholinyl,1,4-oxazepanyl, piperdinyl, C1-C3 alkyl-substituted piperidinyl (e.g.,methylpiperidinyl), acylpiperdinyl, cyanopiperdinyl,cycloalkylpiperdinyl, halopiperdinyl (e.g., fluoropiperdinyl),dihalopiperdinyl (e.g., difluoropiperdinyl), alkoxypiperdinyl,pyrrolidonyl, piperidonyl, thiomorpholinyl-1,1-dioxide,3-azabicyclo[3.1.0]hexanyl, oxa-5-azabicyclo[2.2.1]heptan-5-yl, andazabicyclo[2.2.1]heptan-2-yl.

In one embodiment, Y is O and R² is heteroarylalkyl optionallysubstituted with one or more R⁹. In one embodiment, the heteroarylportion of the heteroarylalkyl is pyridinyl.

In one embodiment, Y is O and R² is —ZR⁵R¹⁰. In one embodiment, R⁵ isC1-C3 alkyl and R¹⁰ is independently selected from acyl, hydroxyalkyl oralkoxy.

In one embodiment, Y is a bond and R² is hydrogen, heterocyclyl or aryl,wherein said heterocyclyl and aryl are optionally substituted with oneor more R⁹.

In one embodiment, Y is a bond and R² is hydrogen.

In one embodiment, Y is a bond and R² is heterocyclyl optionallysubstituted with one or more R⁹. In one embodiment, Y is a bond and R²is heterocyclyl optionally substituted with methyl, halogen ordimethylamino. Nonlimiting examples of R heterocyclyls includeazetidinyl, piperidinyl, piperazinyl, morpholinyl, and pyrrolidinyl.

In one embodiment, Y is a bond and R is aryl optionally substituted withone or more R⁹. In one embodiment, the aryl is phenyl substituted withheterocyclylalkyl.

In certain other embodiments when X is a monocyclic ring, R⁴ is aryl. Inone embodiment, R⁴ is selected from the group consisting of phenyl andnaphthyl and is optionally substituted with one or more R⁶ or R⁷.Examples of R⁷ substituents include halogen, hydroxyl, C1-C6 alkyl(e.g., C1-C3 alkyl), cycloalkyl, haloalkyl, Q-haloalkyl, amino, cyano,hydroxyalkyl and alkoxy. In one embodiment, the aryl is phenylsubstituted with one or more R⁷ groups independently selected fromhalogen, hydroxyl, C1-C3 alkyl, haloalkyl, Q-haloalkyl, and alkoxy. Inone embodiment, the aryl is phenyl substituted with one or more R⁷groups independently selected from halogen, haloalkyl, methyl,isopropyl, methoxy, Q-haloalkyl and hydroxyl. In one embodiment, thearyl is phenyl substituted with one or more R⁷ groups independentlyselected from methyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxyl,trifluoromethoxy, hydroxyl, fluoro, chloro, isopropyl, cyclopropyl andtrifluoromethylthio. In one embodiment, the aryl is phenyl substitutedwith one to three R⁷ groups independently selected from hydroxyl,fluorine and chlorine. In one embodiment, the aryl is phenyl substitutedwith hydroxyl and C1-C3 alkyl or two C1-C3 alkyl. In one embodiment, thearyl is phenyl substituted with Q-haloalkyl and hydroxyl or fluorine.

In one embodiment, R⁴ is aryl wherein aryl is naphthyl optionallysubstituted with one or more R⁷. In one embodiment, the aryl is naphthylsubstituted with one or more R⁷ groups independently selected fromhalogen, hydroxyl, C1-C3 alkyl, haloalkyl, Q-haloalkyl, and alkoxy. Inone embodiment, the aryl is naphthyl substituted with one or more R⁷groups independently selected from halogen, haloalkyl, methyl,isopropyl, methoxy, Q-haloalkyl and hydroxyl. In one embodiment, R⁴ isnaphthyl optionally substituted with one or more R⁷ substituentsindependently selected from hydroxyl, halogen, C1-C3 alkyl, amino, andhaloalkyl. In one embodiment, R⁴ is naphthyl optionally substituted withone to three R⁷ substituents independently selected from difluoromethyl,methyl, hydroxyl, amino, fluoro, and chloro.

In one embodiment, the aryl is naphthyl optionally substituted with oneor more halogen. In one embodiment, the aryl is naphthyl substitutedwith hydroxyl and trifluoromethyl or C1-C3alkyl. In one embodiment, thearyl is naphthyl substituted with hydroxyl.

In one embodiment, R⁴ is heteroaryl optionally substituted with one ormore R⁷. In one embodiment, R⁴ is heteroaryl optionally substituted withone or more R⁷ independently selected from halogen, hydroxyl, C1-C3alkyl, haloalkyl, Q-haloalkyl, alkoxy and amino. In one embodiments, R⁴is indoyl, indazolyl, quinolinyl, isoquinolinyl, pyridinyl orbenzo[d]thiazolyl optionally substituted with one or more R⁷. In oneembodiments, R⁴ is indoyl, indazolyl, quinolinyl, isoquinolinyl,pyridinyl or benzo[d]thiazolyl optionally substituted with one or moreR⁷ independently selected from halogen, hydroxyl, C1-C3 alkyl,haloalkyl, Q-haloalkyl, alkoxy and amino.

In yet other embodiments, R⁴ is heteroaryl, optionally an indoyl or anindazolyl, each of which may be substituted with one or more R⁷. In oneembodiment, R⁴ is heteroaryl optionally substituted with one or more R⁷substituents independently selected from the group consisting ofhalogen, hydroxyl, C1-C3 alkyl, haloalkyl, Q-haloalkyl and alkoxy. Inone embodiment, the R⁴ heteroaryl is indazolyl optionally substitutedwith one or two R⁷ independently selected from alkoxy, haloalkyl, andC1-C6 alkyl. In other embodiments, the R⁴ heteroaryl is a quinolinyl orisoquinolinyl, each optionally substituted with one or more R⁷. In oneembodiment, the R⁴ heteroaryl is a quinolinyl or isoquinolinyl, eachoptionally substituted with one or more R⁷ independently selected fromamino, hydroxyl, C1-C3 alkyl, and hydroxyl. In one embodiment, the R⁴heteroaryl is a quinolinyl or isoquinolinyl, each optionally substitutedwith R⁷ selected from hydroxyl and amino. In one embodiment, the R⁴heteroaryl is a pyridinyl optionally substituted with one or more R⁷. Inone embodiment, the R⁴ heteroaryl is pyridinyl optionally substitutedwith one or more R⁷ independently selected from C1-C3 alkyl, halogen andhaloalkyl. In other embodiments, the R⁴ heteroaryl is benzo[d]thiazolyloptionally substituted with one or more R⁷, such as hydroxyl, one or twoC1-C3 alkyl, or hydroxyl and one or two C1-C3 alkyl. In one embodiment,the R⁴ heteroaryl is indolyl optionally substituted with one or more R⁷.In one embodiment, the R⁴ heteroaryl is indolyl optionally substitutedwith one or two R⁷ independently selected from hydroxyl and C1-C3alkyl.

In one embodiment, where X is a monocyclic ring, R⁴ is aralkyl. Incertain embodiments, the aralkyl is benzyl. In other embodiments, thealkyl of the benzyl group is optionally substituted with hydroxyalkyl.

In one embodiment, L is a bond.

In one embodiment, m is one and R³ is C1-C3 alkyl.

In one embodiment, m is one and R³ is oxo.

In one embodiment, R⁸ is heteroalkyl, C2-C4 alkynyl or C1-C3 alkyloptionally substituted with —OR⁵, cyano or heteroaryl. In oneembodiment, R⁸ is methyl, cyanomethyl, methoxymethyl, hydroxymethyl. Inone embodiment, R⁸ is methyl. In one embodiment, R⁸ is cyanomethyl. Inone embodiment, R⁸ is hydroxymethyl.

In one embodiment, Formula I includes compounds having the Formula I-A:

-   -   wherein R¹, R³, R⁴, R⁵, R¹⁰, L and m are as defined for Formula        I, R¹¹ is hydrogen, methyl or hydroxyalkyl, and the piperidinyl        ring is optionally substituted with R⁸ wherein R⁸ is as defined        for Formula I. In one embodiment, L is a bond. In one        embodiment, R⁴ is aryl or heteroaryl, each of which is        optionally substituted with one or more R⁶ or R⁷. In one        embodiment, R⁴ is aryl or heteroaryl, each of which is        optionally substituted with one or more R⁷. In one embodiment,        each R⁷ is independently selected from hydroxyl, amino, halogen,        C1-C3 alkyl, haloalkyl, Q-haloalkyl, cycloalkyl and alkoxy. In        one embodiment, R⁵ and R¹⁰ are each C1-C3 alkyl. In one        embodiment, the aryl is phenyl substituted with one or more R⁷        groups independently selected from halogen, hydroxyl, C1-C3        alkyl, haloalkyl, Q-haloalkyl, and alkoxy. In one embodiment,        the aryl is phenyl substituted with one or more R⁷ groups        independently selected from halogen, haloalkyl, methyl,        isopropyl, methoxy, Q-haloalkyl and hydroxyl. In one embodiment,        the aryl is phenyl substituted with one or more R⁷ groups        independently selected from methyl, trifluoromethyl,        2,2,2-trifluoroethyl, hydroxyl, trifluoromethoxy, hydroxyl,        fluoro, chloro, isopropyl, cyclopropyl and trifluoromethylthio.        In one embodiment, the aryl is phenyl substituted with one to        three R⁷ groups independently selected from hydroxyl, fluorine        and chlorine. In one embodiment, the aryl is phenyl substituted        with hydroxyl and C1-C3 alkyl or two C1-C3 alkyl. In one        embodiment, the aryl is phenyl substituted with Q-haloalkyl and        hydroxyl or fluorine. In one embodiment, the aryl is naphthyl        substituted with one or more R⁷ groups independently selected        from halogen, hydroxyl, C1-C3 alkyl, haloalkyl, Q-haloalkyl, and        alkoxy. In one embodiment, the aryl is naphthyl substituted with        one or more R⁷ groups independently selected from halogen,        haloalkyl, methyl, isopropyl, methoxy, Q-haloalkyl and hydroxyl.        In one embodiment, R⁴ is naphthyl optionally substituted with        one or more R⁷ substituents independently selected from        hydroxyl, halogen, C1-C3 alkyl, amino, and haloalkyl. In one        embodiment, R⁴ is naphthyl optionally substituted with one to        three R⁷ substituents independently selected from        difluoromethyl, methyl, hydroxyl, amino, fluoro, and chloro. In        one embodiment, the aryl is naphthyl optionally substituted with        one or more halogen. In one embodiment, the aryl is naphthyl        substituted with hydroxyl and trifluoromethyl or C1-C3alkyl. In        one embodiment, the aryl is naphthyl substituted with hydroxyl.        In one embodiment, R⁴ is heteroaryl, wherein the heteroaryl is        indazolyl optionally substituted with one or two R⁷        independently selected from alkoxy, haloalkyl, and C1-C6 alkyl.        In one embodiment, R⁴ is heteroaryl, wherein the heteroaryl is        quinolinyl or isoquinolinyl, each optionally substituted with        one or more R⁷. In one embodiment, R⁴ is heteroaryl, wherein the        heteroaryl is quinolinyl or isoquinolinyl, each optionally        substituted with one or more R⁷ independently selected from        amino, hydroxyl, C1-C3alkyl, and hydroxyl. In one embodiment,        the R⁴ heteroaryl is a pyridinyl optionally substituted with one        or more R⁷. In one embodiment, the R⁴ heteroaryl is pyridinyl        optionally substituted with one or more R⁷ independently        selected from C1-C3 alkyl, halogen and haloalkyl. In one        embodiment, the R⁴ heteroaryl is benzo[d]thiazolyl optionally        substituted with one or more R⁷, such as hydroxyl, one or two        C1-C3 alkyl, or hydroxyl and one or two C1-C3 alkyl. In one        embodiment, the R⁴ heteroaryl is indolyl optionally substituted        with one or more R⁷. In one embodiment, the R⁴ heteroaryl is        indolyl optionally substituted with one or two R⁷ independently        selected from hydroxyl and C1-C3alkyl. In one embodiment, R¹¹ is        methyl. In one embodiment, the piperidinyl ring is        unsubstituted. In one embodiment, the piperidinyl ring is        substituted with R⁸. In one embodiment, R⁸ is C1-C3 alkyl        optionally substituted with cyano or hydroxyl. In one        embodiment, R⁸ is methyl, cyanomethyl or hydroxymethyl. In one        embodiment, R⁸ is methyl. In one embodiment, R⁸ is cyanomethyl.        In one embodiment, R⁸ is hydroxymethyl. In another embodiment,        R⁵ and R¹⁰ are each C1-C3 alkyl, R¹¹ is methyl, R⁸ is methyl,        cyanomethyl or hydroxymethyl, L is a bond, and R⁴ is aryl or        heteroaryl, each optionally substituted with one or more R⁶ or        R⁷.

In one embodiment, Formula I includes compounds having the Formula I-B:

and R¹, R³, R⁴, R⁹, L and m are as defined for Formula I, R² isheterocyclylalkyl optionally substituted with one or more R⁹, and thepiperidinyl ring is optionally substituted with R⁸, where R⁸ is asdefined for Formula I. In one embodiment, the heterocyclyl portion ofthe R² heterocyclylalkyl is a monocyclic, bicyclic, or bridged ringsystem having one or two ring heteroatoms independently selected from Nand O. In one embodiment, R² heterocyclyl is pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, 1,4-oxazepanyl, thiomorpholinyl-1,1-dioxide,3-azabicyclo[3.1.0]hexanyl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, andazabicyclo[2.2.1]heptan-2-yl, optionally substituted with one or moreR⁹. In one embodiment, each R⁹ is selected from acyl, oxo, halogen,cyano, C1-C3 alkyl, alkoxy, hydroxyalkyl, heteroalkyl, heterocyclyl,cycloalkyl, aralkyl and dialkylamidoalkyl. In one embodiment, L is abond. In one embodiment, R⁴ is aryl or heteroaryl, each of which isoptionally substituted with one or more R⁶ or R⁷. In one embodiment, R⁴is aryl or heteroaryl, each of which is optionally substituted with oneor more R⁷. In one embodiment, each R⁷ is independently selected fromhydroxyl, amino, halogen, C1-C3 alkyl, haloalkyl, Q-haloalkyl,cycloalkyl and alkoxy. In one embodiment, the aryl is phenyl substitutedwith one or more R⁷ groups independently selected from halogen,hydroxyl, C1-C3 alkyl, haloalkyl, Q-haloalkyl, and alkoxy. In oneembodiment, the aryl is phenyl substituted with one or more R⁷ groupsindependently selected from halogen, haloalkyl, methyl, isopropyl,methoxy, Q-haloalkyl and hydroxyl. In one embodiment, the aryl is phenylsubstituted with one or more R⁷ groups independently selected frommethyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxyl,trifluoromethoxy, hydroxyl, fluoro, chloro, isopropyl, cyclopropyl andtrifluoromethylthio. In one embodiment, the aryl is phenyl substitutedwith one to three R⁷ groups independently selected from hydroxyl,fluorine and chlorine. In one embodiment, the aryl is phenyl substitutedwith hydroxyl and C1-C3 alkyl or two C1-C3 alkyl. In one embodiment, thearyl is phenyl substituted with Q-haloalkyl and hydroxyl or fluorine. Inone embodiment, the aryl is naphthyl substituted with one or more R⁷groups independently selected from halogen, hydroxyl, C1-C3 alkyl,haloalkyl, Q-haloalkyl, and alkoxy. In one embodiment, the aryl isnaphthyl substituted with one or more R⁷ groups independently selectedfrom halogen, haloalkyl, methyl, isopropyl, methoxy, Q-haloalkyl andhydroxyl. In one embodiment, R⁴ is naphthyl optionally substituted withone or more R⁷ substituents independently selected from hydroxyl,halogen, C1-C3 alkyl, amino, and haloalkyl. In one embodiment, R⁴ isnaphthyl optionally substituted with one to three R⁷ substituentsindependently selected from difluoromethyl, methyl, hydroxyl, amino,fluoro, and chloro. In one embodiment, the aryl is naphthyl optionallysubstituted with one or more halogen. In one embodiment, the aryl isnaphthyl substituted with hydroxyl and trifluoromethyl or C1-C3alkyl. Inone embodiment, the aryl is naphthyl substituted with hydroxyl. In oneembodiment, R⁴ is heteroaryl, wherein the heteroaryl is indazolyloptionally substituted with one or two R⁷ independently selected fromalkoxy, haloalkyl, and C1-C6 alkyl. In one embodiment, R⁴ is heteroaryl,wherein the heteroaryl is quinolinyl or isoquinolinyl, each optionallysubstituted with one or more R⁷. In one embodiment, R⁴ is heteroaryl,wherein the heteroaryl is quinolinyl or isoquinolinyl, each optionallysubstituted with one or more R⁷ independently selected from amino,hydroxyl, C1-C3 alkyl, and hydroxyl. In one embodiment, the R⁴heteroaryl is a pyridinyl optionally substituted with one or more R⁷. Inone embodiment, the R⁴ heteroaryl is pyridinyl optionally substitutedwith one or more R⁷ independently selected from C1-C3 alkyl, halogen andhaloalkyl. In one embodiment, the R⁴ heteroaryl is benzo[d]thiazolyloptionally substituted with one or more R⁷, such as hydroxyl, one or twoC1-C3 alkyl, or hydroxyl and one or two C1-C3 alkyl. In one embodiment,the R heteroaryl is indolyl optionally substituted with one or more R⁷.In one embodiment, the R⁴ heteroaryl is indolyl optionally substitutedwith one or two R⁷ independently selected from hydroxyl and C1-C3 alkyl.In one embodiment, R¹¹ is methyl. In one embodiment, the piperidinylring is unsubstituted. In one embodiment, the piperidinyl ring issubstituted with R⁸. In one embodiment, the piperidinyl ring isunsubstituted. In one embodiment, the piperidinyl ring is substitutedwith R⁸. In one embodiment, R⁸ is C1-C3 alkyl optionally substitutedwith cyano, hydroxyl or methoxy. In one embodiment, R⁸ is methyl,cyanomethyl, hydroxymethyl or methoxymethyl.

In one embodiment, X is a saturated bridged ring system. Nonlimitingexamples of bridged ring systems include diazabicycloheptanes anddiazabicyclooctanes. In certain embodiments, when X is a saturatedbridged ring system, R¹ is —C(O)CH═CH₂. In one embodiment, the bridgedring system is substituted with one or two groups independently selectedfrom R⁸, where R⁸ is as defined for Formula I. In one embodiment, thebridged ring system is unsubstituted. In one embodiment, the bridgedring system is diazabicyclo[3.2.1]octan-8-yl ordiazabicyclo[3.2.1]octan-3-yl.

In one embodiment, R¹—X is:

-   -   wherein A and B are a spirocyclic ring system, wherein A and B        are the same or different and independently represent a 4-6        membered saturated ring systems, wherein the rings are        optionally substituted with one or more R⁸, wherein R⁸ is as        defined for Formula I. In certain embodiments, R¹ is        —C(O)CH═CH₂. In certain embodiments, rings A and B are        unsubstituted.

In one embodiment, the spirocyclic ring system is unsubstituted.Non-limiting examples of spirocyclic ring systems include.

In certain embodiments when A and B represent a spirocyclic ring system,R¹ is —C(O)CH═CH₂.

In one embodiment of Formula I, R² is selected from the group consistingof hydroxyalkyl, dialkylaminylalkyl, heterocyclyl and heterocyclylalkyl,wherein each of the heterocyclyl or heterocyclylalkyl are independentlyoptionally substituted with R⁹. In another embodiment, R² isheterocyclyl and heterocyclylalkyl, wherein each of the heterocyclyl orheterocyclylalkyl are independently optionally substituted with one ormore R⁹. In certain embodiments, R² is dialkylaminylalkyl optionallysubstituted with one or more R⁹. Non-limiting examples includedimethylaminylethyl, dimethylaminylpropanyl, dimethylaminylpropan-2-yl,dimethylaminylbutanyl, dimethylaminylbutan-2-yl,2-dimethylaminylpropanol, or diethylaminylethyl.

In one embodiment, Y is O and R² is selected from the group consistingof hydroxyalkyl, dialkylaminylalkyl, heterocyclyl, heterocyclylalkyl,and —ZR⁵R¹⁰, wherein R⁵ and R¹⁰ are as defined for Formula I.

In one embodiment, Y is O and R² is selected from the group consistingof hydroxyalkyl, dialkylaminylalkyl, heterocyclyl and heterocyclylalkyl,wherein each of the heterocyclyl or heterocyclylalkyl are independentlyoptionally substituted with R⁹. In another embodiment, R² isheterocyclyl and heterocyclylalkyl, wherein each of the heterocyclyl orhetercxyclylalkyl are independently optionally substituted with one ormore R⁹. Non-limiting examples of R⁹ include acyl, oxo, halogen, cyano,C1-C6 alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, aralkyl ordialkylamidoalkyl. In certain embodiments, R² is dialkylaminylalkyloptionally substituted with one or more R⁹. Non-limiting examplesinclude dimethylaminylethyl, dimethylaminylpropanyl,dimethylaminylpropan-2-yl, dimethylaminylbutanyl,dimethylaminylbutan-2-yl, 2-dimethylaminylpropanol, ordiethylaminylethyl.

In one embodiment of Formula I, R⁴ is aryl optionally substituted withone or more R⁶ or R⁷. In one embodiment, R⁴ is phenyl or naphthyloptionally substituted with one or more R⁶ or R⁷. In one embodiment, R⁴is phenyl or naphthyl optionally substituted with one or more R⁷. In oneembodiment, R⁴ is phenyl or naphthyl optionally substituted with one ormore R⁷ substituents independently selected from halogen, hydroxyl,C1-C3alkyl, cycloalkyl, alkoxy, haloalkyl, or Q-haloalkyl wherein Q is Oor S. In one embodiment, R⁴ is phenyl or naphthyl optionally substitutedwith one or more R⁷ substituents independently selected from methyl,trifluoromethyl, hydroxyl, trifluoromethoxy, hydroxyl, fluoro, chloro,isopropyl, cyclopropyl and methylthio.

In one embodiment, R⁴ is isoquinolinyl which is optionally substitutedwith amino. In one embodiment, R⁴ is aralkyl. In certain embodiments,the aralkyl is benzyl. In one embodiment, the aralkyl is benzyl whereinthe alkyl portion is substituted with hydroxyl or hydroxyalkyl.

Nonlimiting examples of compounds of Formula (I), Formula I-A andFormula I-B are selected from the group consisting of:

-   -   and pharmaceutically acceptable salts thereof.

Further nonlimiting examples of compounds of Formula (I), Formula I-Aand Formula I-B are selected from the group consisting of:

-   -   and pharmaceutically acceptable salts thereof.

In one aspect of the invention, compounds are provided represented byformula (II):

-   -   or a pharmaceutically acceptable salt thereof:    -   wherein:    -   X is a 4-12 membered saturated or partially saturated        monocyclic, bridged or spirocyclic ring, wherein the saturated        or partially saturated monocyclic ring is optionally substituted        with one or more R⁸;    -   Y is a bond, O, S or NR⁵;    -   R¹ is —C(O)C(R^(A))        C(R^(B))_(p) or —SO₂C(R^(A))        C(R^(B))_(p);    -   R² is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl,        alkylaminylalkyl, dialkylaminylalkyl, —Z—NR⁵R¹⁰, heterocyclyl,        heterocyclylalkyl, aryl, heteroaryl, or heteroarylalkyl, wherein        each of the Z, heterocyclyl, heterocyclylalkyl, aryl,        heteroaryl, and heteroarylalkyl may be optionally substituted        with one or more R⁹;    -   each Z is C1-C4 alkylene;    -   each R³ is independently C1-C3 alkyl, oxo, haloalkyl, hydroxyl        or halogen;    -   L is a bond, —C(O)—, or C1-C3 alkylene;    -   R⁴ is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl or        heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl,        aralkyl and heteroaryl may be optionally substituted with one or        more R⁶, R⁷ or R⁸;    -   each R⁵ is independently hydrogen or C1-C3 alkyl;    -   R⁶ is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or        heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl,        or heteroaryl may be optionally substituted with one or more R⁷;    -   each R⁷ is independently halogen, hydroxyl, C1-C6 alkyl,        cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl,        hydroxyalkyl or Q-haloalkyl, wherein Q is O or S;    -   R⁸ is oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano,        —C(O)OR⁵, —C(O)N(R⁵)₂, —N(R⁵)₂, wherein the C1-C3 alkyl may be        optionally substituted with cyano, halogen, —OR⁵, —N(R⁵)₂, or        heteroaryl;    -   each R⁹ is independently hydrogen, oxo, acyl, hydroxyl,        hydroxyalkyl, cyano, halogen, C1-C6 alkyl, aralkyl, haloalkyl,        heteroalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl,        alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl,        wherein the C1-C6 alkyl may be optionally substituted with        cycloalkyl;    -   each R¹⁰ is independently hydrogen, acyl, C1-C3 alkyl,        heteroalkyl or hydroxyalkyl;    -   R¹¹ is haloalkyl;    -   R^(A) is absent, hydrogen, deuterium, cyano, halogen, C1-C-3        alkyl, haloalkyl, heteroalkyl, —C(O)N(R⁵)₂, or hydroxyalkyl;    -   each R^(B) is independently hydrogen, deuterium, cyano, C1-C3        alkyl, hydroxyalkyl, heteroalkyl, C1-C3 alkoxy, halogen,        haloalkyl, —ZNR⁵R¹¹, —C(O)N(R⁵)₂, —NHC(O)C1-C3 alkyl,        —CH₂NHC(O)C1-C3 alkyl, heteroaryl, heteroarylalkyl,        dialkylaminylalkyl, or heterocyclylalkyl wherein the        heterocyclyl portion is substituted with one or more        substituents independently selected from halogen, hydroxyl,        alkoxy and C1-C3 alkyl, wherein the heteroaryl or the heteroaryl        portion of the heteroarylalkyl is optionally substituted with        one or more R⁷;    -   or when        is a double bond and p is two, one R^(B) is hydrogen and R^(A)        and one R^(B) and the carbon atoms to which they are attached        form a 4-8 membered partially saturated cycloalkyl substituted        with oxo;    -   m is zero or an integer between 1 and 2;    -   p is one or two; and wherein,    -   when        is a triple bond then R^(A) is absent, p equals one and R^(B) is        hydroxyalkyl,    -   or when        is a double bond then R^(A) is present, R^(B) is present and p        equals two, wherein when R^(A) is hydrogen or C1-C3 alkyl, at        least one R^(B) is deuterium, cyano, halogen, haloalkyl,        hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl,        —ZNR⁵R¹¹, —C(O)N(R⁵)₂, —NHC(O)C1-C3 alkyl, —CH₂NHC(O)C1-C3 alkyl        or heterocyclylalkyl, wherein the heterocyclyl portion is        substituted with one or more substituents independently selected        from halogen, hydroxyl, alkoxy and C1-C3 alkyl; or when each        R^(B) is hydrogen, then R^(A) is deuterium, cyano, halogen,        haloalkyl, —C(O)N(R⁵)₂, hydroxyalkyl or heteroalkyl.

In certain embodiments, R¹—X is:

-   -   wherein R¹ is are defined for Formula II and the piperazinyl        ring is optionally substituted with R⁸, where R⁸ is as defined        for Formula II. In certain embodiments, R⁸ is C1-C3 alkyl        wherein the alkyl is optionally substituted with cyano or OR⁵,        or —C(O)N(R⁵)₂, wherein each R⁵ is independently hydrogen or        C1-C3 alkyl.

In particular embodiments, R¹ is —C(O)C(R^(A))

C(R^(B))_(p) where R^(A), R^(B) and p are as defined for Formula II. Inone embodiment, R¹ is —C(O)C(R^(A))

C(R^(B))_(p), wherein

is a triple bond and R^(A) is absent, p is one and R^(B) ishydroxyalkyl.

In one embodiment, R¹ is —C(O)C(R^(A))

C(R^(B))_(p), wherein

is a double bond and R^(A) is hydrogen or C1-C3 alkyl, p is two and atleast one R^(B) is deuterium, cyano, C1-C3 alkyl, hydroxyalkyl,heteroalkyl, C1-C3 alkoxy, halogen, haloalkyl, —ZNR⁵R¹¹, —C(O)N(R⁵)₂,—NHC(O)C1-C3 alkyl, —CH₂NHC(O)C1-C3 alkyl, heteroaryl, heteroarylalkyl,dialkylaminylalkyl, or heterocyclylalkyl wherein the heterocyclylportion is substituted with one or more substituents independentlyselected from halogen, hydroxyl, alkoxy and C1-C3 alkyl, wherein theheteroaryl or the heteroaryl portion of the heteroarylalkyl isoptionally substituted with one or more R⁷. In one embodiment, when

is a double bond, the double bond is in the E configuration. In oneembodiment, the double bond is in the Z configuration.

In certain embodiments, one R^(B) is heterocyclylalkyl substituted withone or more substituents independently selected from halogen, hydroxyl,alkoxy or C1-C3 alkyl and the other R^(B) is hydrogen. In oneembodiment, the heterocyclyl portion of the heterocyclylalkyl isazetidinyl substituted with a halogen. In certain embodiments, thehalogen is fluorine. In one embodiment, the heterocyclyl portion of theheterocyclylalkyl is pyrrolidinyl substituted with one or more halogen.In certain embodiments, the halogen-substituted pyrrolidinyl isfluoropyrrolidinyl or difluorpyrrolidinyl.

In certain embodiments, one R^(B) is halogen and the other R^(B) ishydrogen. In one embodiment, the halogen is chlorine.

In certain embodiments, one R^(B) is haloalkyl and the other R^(B) ishydrogen. In one embodiment, the haloalkyl is chloromethyl,fluoromethyl, difluoromethyl or trifluoromethyl.

In certain embodiments, one R^(B) is heteroalkyl and the other R^(B) ishydrogen. In one embodiment, the heteroalkyl is methoxymethyl.

In certain embodiments, one R^(B) is —ZNR⁵R¹¹, wherein Z is methylene,R⁵ is methyl and R¹¹ is trifluoromethyl or 2,2,2-trifluoroethyl, and theother R^(B) is hydrogen.

In certain embodiments, one R^(B) is hydroxyalkyl and the other R^(B) ishydrogen.

In certain embodiments, one R^(B) is heteroaryl optionally substitutedwith one or more R⁷ and the other R^(B) is hydrogen. In one embodiment,the heteroaryl is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, each substituted withone or more R⁷.

In certain embodiments, one R^(B) is heteroarylalkyl optionallysubstituted with one or more R⁷, and the other R^(B) is hydrogen. In oneembodiment, the heteroaryl portion of the heteroarylalkyl is pyrrolyl,imidazolyl, pyrazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl or triazinyl, each optionally substituted with one or more R⁷.In one embodiment, the one or more R⁷ is C1-C3 alkyl.

In certain embodiments, one R^(B) is —C(O)N(R⁵)₂ and the other R^(B) ishydrogen. In one embodiment, each R⁵ is hydrogen. In one embodiment,each R⁵ is C1-C3 alkyl.

In certain embodiments, one R^(B) is —NHC(O)C1-C3 alkyl or—CH₂NHC(O)C1-C3 alkyl and the other R^(B) is hydrogen. In oneembodiment, the C1-C3 alkyl is methyl.

In one embodiment, R¹ is —C(O)C(R^(A))═C(R^(B))_(p), wherein R^(A) isdeuterium, cyano, halogen, C1-C-3 alkyl, haloalkyl, heteroalkyl,—C(O)N(R⁵)₂, or hydroxyalkyl, p is two, each R^(B) is hydrogen. In oneembodiment, R^(A) is halogen. In one embodiment, the halogen is fluorineor chlorine. In one embodiment, R^(A) is haloalkyl. In one embodiment,the haloalkyl is trifluoromethyl. In one embodiment, R^(A) is cyano. Inone embodiment, R^(A) is heteroalkyl. In one embodiment, the heteroalkylis methoxy. In one embodiment, R^(A) is hydroxyalkyl.

In one embodiment, R¹ is —C(O)C(R^(A))

C(R^(B))_(p), wherein

is a double bond and R^(A) is deuterium, p is two and at least one R^(B)is deuterium.

In one embodiment, R¹ is —C(O)C(R^(A))

C(R^(B))_(p), wherein

is a double bond and p is two, one R^(B) is hydrogen and R^(A) and oneR^(B) and the carbon atoms to which they are attached form a 5-8membered partially saturated cycloalkyl substituted with oxo.

In one embodiment, R¹ is —C(O)C(R^(A))

C(R^(B))_(p), wherein

is a double bond and p is two, one R^(B) is hydrogen, the second R^(B)is dialkylaminylalkyl, and R^(A) is halogen.

In one embodiment, Y is O or NR⁵ and R² is heterocyclyl orheterocyclylalkyl optionally substituted with one or more R⁹.Nonlimiting examples of one or more R⁹ when R² is heterocyclyl orheterocyclylalkyl include C1-C3 alkyl, acyl, oxo, cyano, alkoxy,cycloalkyl, cycloalkylmethyl, halogen, and hydroxyl. Nonlimitingexamples of R² heterocyclyls optionally substituted with one or more R⁹include azetidinyl, C1-C3 alkyl-substituted azetidinyl (e.g.,methylazetidinyl), halo-substituted azetidinyl (e.g.,difluoroazetidinyl), tetrahydropyran, pyrrolidinyl, C1-C3alkyl-substituted pyrrolidinyl (e.g., methylpyrrolidinyl,dimethylpyrrolidinyl, and isopropylpyrrolidinyl),cycloalkylalkylpyrrolidinyl, hydroxypyrrolindinyl, halo-substitutedpyrrolidinyl (e.g., fluoropyrrolidinyl and difluoropyrrolidinyl),halo-substituted N-methyl pyrrolidinyl (e.g., N-methylfluoropyrrolidinyland N-methyldifluoropyrrolidinyl), methoxyethylpyrrolidinyl,alkoxy-substituted N-methylpyrrolidinyl (e.g.,(N-methyl)methoxypyrrolidinyl), piperazinyl, dimethylaminylpyrrolidinyl,morpholinyl, methylmorpholinyl, 1,4-oxazepanyl, piperdinyl, C1-C3alkyl-substituted piperidinyl (e.g., methylpiperidinyl), acylpiperdinyl,cyanopiperdinyl, cycloalkylpiperdinyl, halopiperdinyl (e.g.,fluoropiperdinyl), dihalopiperdinyl (e.g., difluoropiperdinyl),alkoxypiperdinyl, pyrrolidonyl, piperidonyl,thiomorpholinyl-1,1-dioxide, 3-azabicyclo[3.1.0]hexanyl,oxa-5-azabicyclo[2.2.1]heptan-5-yl, and azabicyclo[2.2.1]heptan-2-yl.

In one embodiment, the heterocycyl portion of the heterocyclylalkyl isN-methylpyrrolidinyl. In one embodiment, the heterocycyl portion of theheterocyclylalkyl is 3,3-difluoro-1-methylpyrrolidinyl.

In certain other embodiments, R⁴ is aryl. In one embodiment, R⁴ isselected from the group consisting of phenyl and naphthyl and isoptionally substituted with one or more R⁶ or R⁷. Examples of R⁷substituents include halogen, hydroxyl, C1-C6 alkyl (e.g., C1-C3 alkyl),cycloalkyl, haloalkyl, Q-haloalkyl, amino, cyano, hydroxyalkyl andalkoxy. In one embodiment, the aryl is phenyl substituted with one ormore R⁷ groups independently selected from halogen, hydroxyl, C1-C3alkyl, haloalkyl, Q-haloalkyl, and alkoxy. In one embodiment, the arylis phenyl substituted with one or more R⁷ groups independently selectedfrom halogen, haloalkyl, methyl, isopropyl, methoxy, Q-haloalkyl andhydroxyl. In one embodiment, the aryl is phenyl substituted with one ormore R⁷ groups independently selected from methyl, trifluoromethyl,hydroxyl, fluoro, and chloro. In one embodiment, the aryl is phenylsubstituted with one to three R⁷ groups independently selected frommethyl, hydroxyl, trifluoromethyl, fluorine and chlorine. In oneembodiment, the aryl is phenyl substituted with hydroxyl and C1-C3 alkylor two C1-C3 alkyl. In one embodiment, the aryl is phenyl substitutedwith trifluoromethyl and C1-C3 alkyl or two C1-C3 alkyl.

In one embodiment, R⁴ is aryl wherein aryl is naphthyl optionallysubstituted with one or more R⁷. In one embodiment, the aryl is naphthylsubstituted with one or more R⁷ groups independently selected fromhalogen, hydroxyl, C1-C3 alkyl, haloalkyl, Q-haloalkyl, and alkoxy. Inone embodiment, the aryl is naphthyl substituted with one or more R⁷groups independently selected from halogen, haloalkyl, methyl,isopropyl, methoxy, Q-haloalkyl and hydroxyl. In one embodiment, R⁴ isnaphthyl optionally substituted with one or more R substituentsindependently selected from hydroxyl, halogen, C1-C3 alkyl, amino, andhaloalkyl. In one embodiment, R⁴ is naphthyl optionally substituted withone to three R⁷ substituents independently selected from difluoromethyl,methyl, hydroxyl, amino, fluoro, and chloro. In one embodiment, thesubstituted naphthyl is 8-chloronaphthyl or 8-methylnaphthyl.

In one embodiment, the aryl is naphthyl optionally substituted with oneor more halogen. In one embodiment, the aryl is naphthyl substitutedwith hydroxyl and trifluoromethyl or C1-C3alkyl. In one embodiment, thearyl is naphthyl substituted with hydroxyl.

In one embodiment, R⁴ is heteroaryl optionally substituted with one ormore R⁶, R⁷ or R⁸. In one embodiment, R⁴ is heteroaryl optionallysubstituted with one or more R or R independently selected from halogen,hydroxyl, C1-C3 alkyl, haloalkyl, Q-haloalkyl, alkoxy and amino. In oneembodiments, R⁴ is indoyl, indazolyl, quinolinyl, isoquinolinyl,pyridinyl or benzo[d]thiazolyl optionally substituted with one or moreR⁶, R⁷ or R⁸. In one embodiments, R⁴ is indoyl, indazolyl, quinolinyl,isoquinolinyl, pyridinyl or benzo[d]thiazolyl optionally substitutedwith one or more R⁷ or R⁸ independently selected from oxo, halogen,hydroxyl, C1-C3 alkyl, haloalkyl, Q-haloalkyl, alkoxy and amino.

In yet other embodiments, R⁴ is heteroaryl, optionally an indoyl or anindazolyl, each of which may be substituted with one or more R⁶, R⁷ orR⁸. In one embodiment, R⁴ is heteroaryl optionally substituted with oneor more R⁷ or R⁸ substituents independently selected from the groupconsisting of halogen, hydroxyl, C1-C3 alkyl, haloalkyl, Q-haloalkyl andalkoxy. In one embodiment, the R⁴ heteroaryl is indazolyl optionallysubstituted with one or two R⁷ or R⁸ independently selected from oxo,trifluoromethyl, alkoxy, haloalkyl, and C1-C6 alkyl. In otherembodiments, the R heteroaryl is a quinolinyl or isoquinolinyl, eachoptionally substituted with one or more R⁷. In one embodiment, the R⁴heteroaryl is a quinolinyl or isoquinolinyl, each optionally substitutedwith one or more R⁷ independently selected from amino, hydroxyl. C1-C3alkyl, and hydroxyl. In one embodiment, the R⁴ heteroaryl is aquinolinyl or isoquinolinyl, each optionally substituted with R⁷selected from hydroxyl and amino. In one embodiment, the R⁴ heteroarylis a pyridinyl optionally substituted with one or more R⁶, R⁷ or R⁸. Inone embodiment, the R⁴ heteroaryl is pyridinyl optionally substitutedwith one or more R⁴ independently selected from C1-C3 alkyl, halogen andhaloalkyl. In one embodiment, the R⁴ heteroaryl is indolyl optionallysubstituted with one or more R⁶, R⁷ or R⁸. In one embodiment, the R⁴heteroaryl is indolyl optionally substituted with one or two R⁷independently selected from hydroxyl, trifluoromethyl and C1-C3alkyl.

In one embodiment, L is a bond.

In one embodiment, m is zero.

In one embodiment, R⁸ is heteroalkyl, C2-C4 alkynyl or C1-C3 alkyloptionally substituted with —OR⁵, cyano or heteroaryl. In oneembodiment, R⁸ is methyl, cyanomethyl, methoxymethyl, hydroxymethyl. Inone embodiment, R⁸ is methyl. In one embodiment, R⁸ is cyanomethyl. Inone embodiment, R⁸ is hydroxymethyl.

In one embodiment, Formula II includes compounds having the FormulaII-A:

-   -   wherein R¹, R³, R⁴, R⁵, R¹⁰, L and m are as defined for Formula        II, R¹¹ is hydrogen, methyl or hydroxyalkyl, and the piperazinyl        ring is optionally substituted with R⁸ wherein R⁸ is as defined        for Formula II.

In particular embodiments, R¹ is —C(O)C(R^(A))

C(R^(B))_(p) where R^(A), R^(B) and p are as defined for Formula II. Inone embodiment, R¹ is —C(O)C(R^(A))

C(R^(B))_(p), wherein

is a triple bond and R^(A) is absent, p is one and R^(B) ishydroxyalkyl.

In one embodiment, R¹ is —C(O)C(R^(A))

C(R^(B))_(p), wherein

is a double bond and R^(A) is hydrogen or C1-C3 alkyl, p is two and atleast one R^(B) is deuterium, cyano, C1-C3 alkyl, hydroxyalkyl,heteroalkyl, C1-C3 alkoxy, halogen, haloalkyl, —ZNR⁵R¹¹, —C(O)N(R⁵)₂,—NHC(O)C1-C3 alkyl, —CH₂NHC(O)C1-C3 alkyl, heteroaryl, heteroarylalkyl,or heterocyclylalkyl wherein the heterocyclyl portion is substitutedwith one or more substituents independently selected from halogen,hydroxyl, alkoxy and C1-C3 alkyl, wherein the heteroaryl or theheteroaryl portion of the heteroatylalkyl is optionally substituted withone or more R⁷.

In one embodiment, R¹ is —C(O)C(R^(A))═C(R^(B))_(p), wherein R^(A) isdeuterium, cyano, halogen, haloalkyl, heteroalkyl, —C(O)N(R⁵)₂, orhydroxyalkyl, p is two, and each R^(B) is hydrogen. In one embodiment,R^(A) is halogen. In one embodiment, the halogen is fluorine orchlorine. In one embodiment, R^(A) is haloalkyl. In one embodiment, thehaloalkyl is trifluoromethyl. In one embodiment, R^(A) is cyano. In oneembodiment, R^(A) is heteroalkyl. In one embodiment, the heteroalkyl ismethoxymethyl. In one embodiment, R^(A) is hydroxyalkyl.

In one embodiment, R¹ is —C(O)C(R^(A))

C(R^(B))_(p), wherein

is a double bond and R^(A) is deuterium, p is two and at least one R^(B)is deuterium.

In one embodiment, R¹ is —C(O)C(R^(A)

C(R^(B))_(p), wherein

is a double bond and p is two, one R^(B) is hydrogen and R^(A) and oneR^(B) and the carbon atoms to which they are attached form a 5-8membered partially saturated cycloalkyl substituted with oxo.

In one embodiment, R¹ is —C(O)C(R^(A))

C(R^(B))_(p), wherein

is a double bond and p is two, one R^(B) is hydrogen, the second R^(B)is dialkylaminylalkyl, and R^(A) is halogen.

In one embodiment, L is a bond. In one embodiment, R⁴ is aryl orheteroaryl, each of which is optionally substituted with one or more R⁶,R⁷ or R⁸. In one embodiment, R⁴ is aryl or heteroaryl, each of which isoptionally substituted with one or more R⁷. In one embodiment, each R⁷or R⁸ is independently selected from oxo, hydroxyl, amino, halogen,C1-C3 alkyl, haloalkyl, Q-haloalkyl, cycloalkyl and alkoxy. In oneembodiment, R⁵ and R¹⁰ are each C1-C3 alkyl. In one embodiment, the arylis phenyl substituted with one or more R⁷ groups independently selectedfrom halogen, hydroxyl, C1-C3 alkyl, haloalkyl, Q-haloalkyl, and alkoxy.In one embodiment, the aryl is phenyl substituted with one or more R⁷groups independently selected from halogen, haloalkyl, methyl,isopropyl, methoxy, Q-haloalkyl and hydroxyl. In one embodiment, thearyl is phenyl substituted with one or more groups independentlyselected from methyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxyl,trifluoromethoxy, hydroxyl, fluoro, chloro, isopropyl, cyclopropyl andtrifluoromethylthio. In one embodiment, the aryl is phenyl substitutedwith one to three R⁷ groups independently selected from hydroxyl,fluorine and chlorine. In one embodiment, the aryl is phenyl substitutedwith hydroxyl and C1-C3 alkyl or two C1-C3 alkyl. In one embodiment, thearyl is phenyl substituted with Q-haloalkyl and hydroxyl or fluorine. Inone embodiment, the aryl is naphthyl substituted with one or more R⁷groups independently selected from halogen, hydroxyl, C1-C3 alkyl,haloalkyl, Q-haloalkyl, and alkoxy. In one embodiment, the aryl isnaphthyl substituted with one or more R⁷ groups independently selectedfrom halogen, haloalkyl, methyl, isopropyl, methoxy, Q-haloalkyl andhydroxyl. In one embodiment, R⁴ is naphthyl optionally substituted withone or more R⁷ substituents independently selected from hydroxyl,halogen, C1-C3 alkyl, amino, and haloalkyl. In one embodiment, R⁴ isnaphthyl optionally substituted with one to three R⁷ or R⁸ substituentsindependently selected from difluoromethyl, methyl, hydroxyl, amino,fluoro, and chloro. In one embodiment, the aryl is naphthyl optionallysubstituted with one or more halogen. In one embodiment, the aryl isnaphthyl substituted with hydroxyl and trifluoromethyl or C1-C3alkyl. Inone embodiment, the aryl is naphthyl substituted with hydroxyl. In oneembodiment, R⁴ is heteroaryl, wherein the heteroaryl is indazolyloptionally substituted with one or two R⁷ or R⁸ independently selectedfrom oxo, alkoxy, haloalkyl, and C1-C6 alkyl. In one embodiment, R⁴ isheteroaryl, wherein the heteroaryl is quinolinyl or isoquinolinyl, eachoptionally substituted with one or more R⁷. In one embodiment, R⁴ isheteroaryl, wherein the heteroaryl is quinolinyl or isoquinolinyl, eachoptionally substituted with one or more R⁷ independently selected fromamino, hydroxyl, C1-C3alkyl, and hydroxyl. In one embodiment, the R⁴heteroaryl is a pyridinyl optionally substituted with one or more R⁶, R⁷or R⁸. In one embodiment, the R⁴ heteroaryl is pyridinyl optionallysubstituted with one or more R⁴ independently selected from C1-C3 alkyl,halogen and haloalkyl. In one embodiment, the R⁴ heteroaryl is indolyloptionally substituted with one or more R⁷. In one embodiment, the R⁴heteroaryl is indolyl optionally substituted with one or two R⁷independently selected from hydroxyl and C1-C3alkyl. In one embodiment.R¹¹ is methyl. In one embodiment, the piperazinyl ring is unsubstituted.In one embodiment, the piperazinyl ring is substituted with R⁸. In oneembodiment, R⁸ is C1-C3 alkyl optionally substituted with cyano orhydroxyl. In one embodiment, R⁸ is methyl, cyanomethyl or hydroxymethyl.In one embodiment, R⁸ is methyl. In one embodiment, R⁸ is cyanomethyl.In one embodiment, R⁸ is hydroxymethyl. In another embodiment, R⁵ andR¹⁰ are each C1-C3 alkyl, R¹¹ is methyl, R⁸ is methyl, cyanomethyl orhydroxymethyl, L is a bond, and R⁴ is aryl or heteroaryl, eachoptionally substituted with one or more R⁶ or R⁷.

In one embodiment, Formula II includes compounds having the FormulaII-B:

-   -   where R¹, R³, R⁴, L and in are as defined for Formula II, R² is        heterocyclylalkyl optionally substituted with one or more R⁹        wherein R⁹ is as defined for Formula II, and the piperazinyl        ring is optionally substituted with R⁸, where R⁸ is as defined        for Formula II.

In particular embodiments, R¹ is —C(O)C(R^(A))

C(R^(B))_(p) where R^(A), R^(B) and p are as defined for Formula II. Inone embodiment, R¹ is —C(O)C(R^(A))

C(R^(B))_(p), wherein

is a triple bond and R^(A) is absent, p is one and R^(B) ishydroxyalkyl.

In one embodiment, R¹ is —C(O)C(R^(A))

C(R^(B))_(p), wherein

is a double bond and R^(A) is hydrogen or C1-C3 alkyl, p is two and atleast one R^(B) is deuterium, cyano, C1-C3 alkyl, hydroxyalkyl,heteroalkyl, C1-C3 alkoxy, halogen, haloalkyl, —ZNR⁵R¹¹, —C(O)N(R⁵)₂,—NHC(O)C1-C3 alkyl, —CH₂NHC(O)C1-C3 alkyl, heteroaryl, heteroarylalkyl,or heterocyclylalkyl wherein the heterocyclyl portion is substitutedwith one or more substituents independently selected from halogen,hydroxyl, alkoxy and C1-C3 alkyl, wherein the heteroaryl or theheteroaryl portion of the heteroarylalkyl is optionally substituted withone or more R⁷.

In one embodiment, R¹ is —C(O)C(R^(A))═C(R^(B))_(p), wherein R^(A) isdeuterium, cyano, halogen, haloalkyl, heteroalkyl, —C(O)N(R⁵)₂, orhydroxyalkyl, p is two, and each R^(B) is hydrogen. In one embodiment,R^(A) is halogen. In one embodiment, the halogen is fluorine orchlorine. In one embodiment, R^(A) is haloalkyl. In one embodiment, thehaloalkyl is trifluoromethyl. In one embodiment, R^(A) is cyano. In oneembodiment, R^(A) is heteroalkyl. In one embodiment, the heteroalkyl ismethoxymethyl. In one embodiment, R^(A) is hydroxyalkyl.

In one embodiment, R¹ is —C(O)C(R^(A))

C(R^(B))_(p), wherein

is a double bond and R^(A) is deuterium, p is two and at least one R^(B)is deuterium.

In one embodiment, R¹ is —C(O)C(R^(A))

C(R^(B))_(p), wherein

is a double bond and p is two, one R^(B) is hydrogen and R^(A) and oneR^(B) and the carbon atoms to which they are attached form a 5-8membered partially saturated cycloalkyl substituted with oxo.

In one embodiment, R¹ is —C(O)C(R^(A))

C(R^(B))_(p), wherein

is a double bond and p is two, one R^(B) is hydrogen, the second R^(B)is dialkylaminylalkyl, and R^(A) is halogen.

In one embodiment, the heterocyclyl portion of the R² heterocyclylalkylis a monocyclic, bicyclic, or bridged ring system having one or two ringheteroatoms independently selected from N and O. In one embodiment, R²heterocyclyl is azetidinyl, methylazetidinyl, ethylazetidinyl,isopropylazetidinyl, difluoroazetidinyl, cyclopropylazetidinyl,tetrahydropyranylazetidinyl, tetrahydropyran, pyrrolidinyl,methylpyrrolidinyl, dimethylpyrrolidinyl, isopropylpyrrolidinyl,cycloalkylalkylpyrrolidinyl, hydroxypyrrolindinyl, fluoropyrrolidinyl,difluoropyrrolidinyl, (N-methyl)fluoropyrrolidinyl,(N-methyl)difluoropyrrolidinyl, methoxyethylpyrrolidinyl,alkoxy-substituted N-methylpyrrolidinyl (e.g.,(N-methyl)methoxypyrrolidinyl), piperazinyl, dimethylaminylpyrrolidinyl,pyrrolidinone, methylpyrrolidinone, morpholinyl, methylmorpholinyl,ethylmorpholinyl, isopropylmorpholinyl, oxetanyl, 1,4-oxazepanyl,piperdinyl, methylpiperidinyl acylpiperdinyl, cyanopiperdinyl,cycloalkylpiperdinyl, halopiperdinyl, dihalopiperdinyl,fluoropiperdinyl, difluoropiperdinyl, alkoxypiperdinyl, pyrrolidonyl,piperidinonyl, tetrahydropyrrolizinyl, thiomorpholinyl-1,1-dioxide,3-azabicyclo[3.1.0]hexanyl, oxa-5-azabicyclo[2.2.1]heptan-5-yl, orazabicyclo[2.2.1]heptan-2-yl, optionally substituted with one or moreR⁹. In one embodiment, each R⁹ is selected from acyl, oxo, halogen,cyano, C1-C3 alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl,aralkyl, heterocyclyl and dialkylamidoalkyl. In one embodiment, L is abond. In one embodiment, the heterocyclyl portion of the R²heterocyclylalkyl is (N-methyl)difluoropyrrolidinyl, including3,3-difluoro-1-methylpyrrolidinyl. In one embodiment, the heterocyclylportion of the R² heterocyclylalkyl is N-methylpyrrolidinyl.

In one embodiment, R⁴ is aryl or heteroaryl, each of which is optionallysubstituted with one or more R⁶, R⁷ or R⁸. In one embodiment, R⁴ is arylor heteroaryl, each of which is optionally substituted with one or moreR⁷. In one embodiment, each R⁷ is independently selected from hydroxyl,amino, halogen, C1-C3 alkyl, haloalkyl, Q-haloalkyl, cycloalkyl andalkoxy. In one embodiment, the aryl is phenyl substituted with one ormore R⁷ groups independently selected from halogen, hydroxyl, C1-C3alkyl, haloalkyl, Q-haloalkyl, and alkoxy. In one embodiment, the arylis phenyl substituted with one or more R⁷ groups independently selectedfrom halogen, haloalkyl, methyl, isopropyl, methoxy, Q-haloalkyl andhydroxyl. In one embodiment, the aryl is phenyl substituted with one ormore R⁷ groups independently selected from methyl, trifluoromethyl,2,2,2-trifluoroethyl, hydroxyl, trifluoromethoxy, hydroxyl, fluoro,chloro, isopropyl, cyclopropyl and trifluoromethylthio. In oneembodiment, the aryl is phenyl substituted with one to three R⁷ groupsindependently selected from hydroxyl, fluorine and chlorine. In oneembodiment, the aryl is phenyl substituted with hydroxyl and C1-C3 alkylor two C1-C3 alkyl. In one embodiment, the aryl is phenyl substitutedwith Q-haloalkyl and hydroxyl or fluorine. In one embodiment, the arylis naphthyl substituted with one or more R⁷ groups independentlyselected from halogen, hydroxyl, C1-C3 alkyl, haloalkyl, Q-haloalkyl,and alkoxy. In one embodiment, the aryl is naphthyl substituted with oneor more R⁷ groups independently selected from halogen, haloalkyl,methyl, isopropyl, methoxy, Q-haloalkyl and hydroxyl. In one embodiment,R⁴ is naphthyl optionally substituted with one or more R⁷ substituentsindependently selected from hydroxyl, halogen, C1-C3 alkyl, amino, andhaloalkyl. In one embodiment, R⁴ is naphthyl optionally substituted withone to three R⁷ substituents independently selected from difluoromethyl,methyl, hydroxyl, amino, fluoro, and chloro. In one embodiment, the arylis naphthyl optionally substituted with one or more halogen. In oneembodiment, the aryl is naphthyl substituted with hydroxyl andtrifluoromethyl or C1-C3alkyl. In one embodiment, the aryl is naphthylsubstituted with hydroxyl. In one embodiment, R⁴ is heteroaryl, whereinthe heteroaryl is indazolyl optionally substituted with one or two R⁷independently selected from alkoxy, haloalkyl, and C1-C6 alkyl.

In one embodiment, R⁴ is heteroaryl, wherein the heteroaryl isquinolinyl or isoquinolinyl, each optionally substituted with one ormore R⁶, R⁷ or R⁸. In one embodiment, R⁴ is heteroaryl, wherein theheteroaryl is quinolinyl or isoquinolinyl, each optionally substitutedwith one or more R⁶, R⁷ or R⁸ independently selected from oxo, amino,hydroxyl, C1-C3 alkyl, and hydroxyl. In one embodiment, the R⁴heteroaryl is a pyridinyl optionally substituted with one or more R⁶, R⁷or R⁸. In one embodiment, the R⁴ heteroaryl is pyridinyl optionallysubstituted with one or more R⁷ independently selected from C1-C3 alkyl,halogen and haloalkyl. In one embodiment, the R⁴ heteroaryl is indolyloptionally substituted with one or more R⁶, R⁷ or R⁸. In one embodiment,the R⁴ heteroaryl is indolyl optionally substituted with one or two R⁷independently selected from hydroxyl and C1-C3 alkyl. In one embodiment,R¹¹ is methyl. In one embodiment, the piperazinyl ring is unsubstituted.In one embodiment, the piperazinyl ring of Formula II-B is substitutedwith R⁸. In one embodiment, R⁸ is C1-C3 alkyl optionally substitutedwith cyano, hydroxyl or methoxy. In one embodiment, R⁸ is methyl,cyanomethyl, hydroxymethyl or methoxymethyl.

Nonlimiting examples of compounds of Formula (II), Formula II-A andFormula II-B are selected from the group consisting of:

-   -   or a pharmaceutically acceptable salt thereof.

In one embodiment, the compounds of Formula I include trifluoroaceticacid salts of the above compounds. The compounds of Formula (I), FormulaI-A, Formula I-B, Formula (II), Formula II-A, or Formula II-B may beformulated into pharmaceutical compositions.

Pharmaceutical Compositions

In another aspect, the invention provides pharmaceutical compositionscomprising a KRas G12C inhibitor according to the invention and apharmaceutically acceptable carrier, excipient, or diluent. Compounds ofthe invention may be formulated by any method well known in the art andmay be prepared for administration by any route, including, withoutlimitation, parenteral, oral, sublingual, transdermal, topical,intranasal, intratracheal, or intrarectal. In certain embodiments,compounds of the invention are administered intravenously in a hospitalsetting. In one embodiment, administration may be by the oral route.

The characteristics of the carrier will depend on the route ofadministration. As used herein, the term “pharmaceutically acceptable”means a non-toxic material that is compatible with a biological systemsuch as a cell, cell culture, tissue, or organism, and that does notinterfere with the effectiveness of the biological activity of theactive ingredient(s). Thus, compositions according to the invention maycontain, in addition to the inhibitor, diluents, fillers, salts,buffers, stabilizers, solubilizers, and other materials well known inthe art. The preparation of pharmaceutically acceptable formulations isdescribed in, e.g., Remington's Pharmaceutical Sciences, 18th Edition,ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

As used herein, the term pharmaceutically acceptable salt refers tosalts that retain the desired biological activity of theabove-identified compounds and exhibit minimal or no undesiredtoxicological effects. Examples of such salts include, but are notlimited to acid addition salts formed with inorganic acids (for example,hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,nitric acid, and the like), and salts formed with organic acids such asacetic acid, oxalic acid, tartaric acid, succinic acid, malic acid,ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid,polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid,and polygalacturonic acid. The compounds can also be administered aspharmaceutically acceptable quaternary salts known by those skilled inthe art, which specifically include the quaternary ammonium salt of theformula —NR+Z—, wherein R is hydrogen, alkyl, or benzyl, and Z is acounterion, including chloride, bromide, iodide, —O-alkyl,toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate(such as benzoate, succinate, acetate, glycolate, maleate, malate,citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate,benzyloate, and diphenylacetate).

The active compound is included in the pharmaceutically acceptablecarrier or diluent in an amount sufficient to deliver to a patient atherapeutically effective amount without causing serious toxic effectsin the patient treated. In one embodiment, a dose of the active compoundfor all of the above-mentioned conditions is in the range from about0.01 to 300 mg/kg, for example 0.1 to 100 mg/kg per day, and as afurther example 0.5 to about 25 mg per kilogram body weight of therecipient per day. A typical topical dosage will range from 0.01-3%wt/wt in a suitable carrier. The effective dosage range of thepharmaceutically acceptable derivatives can be calculated based on theweight of the parent compound to be delivered. If the derivativeexhibits activity in itself, the effective dosage can be estimated asabove using the weight of the derivative, or by other means known tothose skilled in the art.

The pharmaceutical compositions comprising compounds of the presentinvention may be used in the methods of use described herein.

Methods of Use

In yet another aspect, the invention provides for methods for inhibitingKRas G12C activity in a cell, comprising contacting the cell in whichinhibition of KRas G12C activity is desired with an effective amount ofa compound of Formula (II), Formula II-A, or Formula II-B,pharmaceutically acceptable salts thereof or pharmaceutical compositionscontaining the compound or pharmaceutically acceptable salt thereof. Inone embodiment, the contacting is in vitro. In one embodiment, thecontacting is in vivo.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” a KRas G12C with a compound provided hereinincludes the administration of a compound provided herein to anindividual or patient, such as a human, having KRas G12C, as well as,for example, introducing a compound provided herein into a samplecontaining a cellular or purified preparation containing the KRas G12C.

In one embodiment, a cell in which inhibition of KRas G12C activity isdesired is contacted with an effective amount of a compound of Formula(II), Formula II-A, or Formula II-B, to negatively modulate the activityof KRas G12C. In other embodiments, a therapeutically effective amountof pharmaceutically acceptable salt or pharmaceutical compositionscontaining the compound of Formula (II), Formula II-A, or Formula II-B,may be used.

By negatively modulating the activity of KRas G12C, the methodsdescribed herein are designed to inhibit undesired cellularproliferation resulting from enhanced KRas G12C activity within thecell. The cells may be contacted in a single dose or multiple doses inaccordance with a particular treatment regimen to effect the desirednegative modulation of KRas G12C. The degree of covalent modification ofKRas G12C may be monitored in vitro using well known methods, includingthose described in Example A below. In addition, the inhibitory activityof exemplary compounds in cells may be monitored, for example, bymeasuring the inhibition of KRas G12C activity of the amount ofphosphylated ERK, including those described in Example B below, toassess the effectiveness of treatment and dosages may be adjustedaccordingly by the attending medical practitioner.

In another aspect, methods of treating cancer in a patient in needthereof, comprising administering to said patient a therapeuticallyeffective amount of a compound of Formula (I). Formula II-A, or FormulaII-B, pharmaceutically acceptable salts thereof or pharmaceuticalcompositions comprising the compound or pharmaceutically acceptablesalts thereof are provided.

The compositions and methods provided herein may be used for thetreatment of a KRas G12C-associated cancer in a patient in need thereof,comprising administering to said patient a therapeutically effectiveamount of a compound of Formula (II), Formula II-A, or Formula II-B,pharmaceutically acceptable salts thereof or pharmaceutical compositionscomprising the compound or pharmaceutically acceptable salts thereof areprovided. In one embodiment, the KRas G12C-associated cancer is lungcancer.

The compositions and methods provided herein may be used for thetreatment of a wide variety of cancers including tumors such as lung,prostate, breast, brain, skin, cervical carcinomas, testicularcarcinomas, etc. More particularly, cancers that may be treated by thecompositions and methods of the invention include, but are not limitedto tumor types such as astrocytic, breast, cervical, colorectal,endometrial, esophageal, gastric, head and neck, hepatocellular,laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas andsarcomas. More specifically, these compounds can be used to treat:Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma,liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung:bronchogenic carcinoma (squamous cell, undifferentiated small cell,undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar)carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatoushamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cellcarcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach(carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma,insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), smallbowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma,leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma,leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor(nephroblastoma), lymphoma, leukemia), bladder and urethra (squamouscell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate(adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonalcarcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cellcarcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver:hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone:osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibroushistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma(reticulum cell sarcoma), multiple myeloma, malignant giant cell tumorchordoma, osteochronfroma (osteocartilaginous exostoses), benignchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma andgiant cell tumors; Nervous system: skull (osteoma, hemangioma,granuloma, xanthoma, osteitis deformans), meninges (meningioma,meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma,glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, congenital tumors),spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological:uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumorcervical dysplasia), ovaries (ovarian carcinoma (serouscystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic:blood (myeloid leukemia (acute and chronic), acute lymphoblasticleukemia, chronic lymphocytic leukemia, myeloproliferative diseases,multiple myeloma, myelodysplastic syndrome), Hodgkin's disease,non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma,basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, molesdysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis;and Adrenal glands: neuroblastoma. In certain embodiments, the cancer isnon-small cell lung cancer.

The concentration and route of administration to the patient will varydepending on the cancer to be treated. The compounds, pharmaceuticallyacceptable salts thereof and pharmaceutical compositions comprising suchcompounds and salts also may be co-administered with otheranti-neoplastic compounds, e.g., chemotherapy, or used in combinationwith other treatments, such as radiation or surgical intervention,either as an adjuvant prior to surgery or post-operatively.

Also provided herein is a compound of Formula I, Formula I-A, FormulaI-B, Formula II, Formula II-A or Formula II-B, or a pharmaceuticallyacceptable salt or solvate thereof, or a pharmaceutical compositionthereof as defined herein for use in therapy.

Also provided herein is a compound of Formula I, Formula I-A, FormulaI-B, Formula II, Formula II-A or Formula II-B, or a pharmaceuticallyacceptable salt or solvate thereof or a pharmaceutical compositionthereof as defined herein for use in the treatment of cancer.

Also provided herein is a compound of Formula I, Formula I-A, FormulaI-B, Formula II, Formula II-A or Formula II-B, or a pharmaceuticallyacceptable salt or solvate thereof for use in the inhibition of KRasG12C.

Also provided herein is a compound of Formula I, Formula I-A, FormulaI-B, Formula II, Formula II-A or Formula II-B, or a pharmaceuticallyacceptable salt or solvate thereof or a pharmaceutical compositionthereof as defined herein, for use in the treatment of a KRasG12C-associated disease or disorder.

Also provided herein is the use of a compound of Formula I, Formula I-A,Formula I-B, Formula II, Formula II-A or Formula II-B, or apharmaceutically acceptable salt or solvate thereof, as defined hereinin the manufacture of a medicament for the treatment of cancer.

Also provided herein is a use of a compound of Formula I, Formula I-A,Formula I-B, Formula II, Formula II-A or Formula II-B, or apharmaceutically acceptable salt or solvate thereof, as defined hereinin the manufacture of a medicament for the inhibition of activity ofKRas G12C.

Also provided herein is the use of a compound of Formula I, Formula I-A,Formula I-B, Formula II, Formula II-A or Formula II-B, or apharmaceutically acceptable salt or solvate thereof, as defined herein,in the manufacture of a medicament for the treatment of a KRasG12C-associated disease or disorder.

Also provided herein is a method for treating cancer in a patient inneed thereof, the method comprising (a) determining that cancer isassociated with a KRas G12C mutation (e.g., a KRas G12C-associatedcancer) (e.g., as determined using a regulatory agency-approved, e.g.,FDA-approved, assay or kit); and (b) administering to the patient atherapeutically effective amount of a compound of Formula I, FormulaI-A, Formula I-B, Formula II, Formula II-A or Formula II-B, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition thereof.

One skilled in the art will recognize that, both in vivo and in vitrotrials using suitable, known and generally accepted cell and/or animalmodels are predictive of the ability of a test compound to treat orprevent a given disorder.

One skilled in the art will further recognize that human clinical trialsincluding first-in-human, dose ranging and efficacy trials, in healthypatients and/or those suffering from a given disorder, may be completedaccording to methods well known in the clinical and medical arts.

REACTION SCHEMES AND EXAMPLES

The compounds of the present invention may be prepared from commerciallyavailable reagents using the synthetic methods and reaction schemesdescribed herein, or using other reagents and conventional methods wellknown to those skilled in the art.

For instance, compounds of the present invention may be preparedaccording to the General Reaction Schemes I and II.

General Reaction Schemes

Compounds of Formula I wherein L, and Y are bonds, R² is hydrogen and R⁴is aryl or heteroaryl can be prepared according to Scheme 1. In step A,an appropriately functionalized dihydropyridopyrimidine (1) is coupledto a heterocycle containing one nucleophilic amine species, with theother bound to a protecting group to provide compound (2). This couplingproceeds in a solvent such as dichloromethane in the presence of a basesuch as triethylamine or Hunig's base. In step B, the Boc group ofcompound (2) is removed using conditions known in the art, for examplewith trifluoroacetic acid in a solvent such as dichloromethane, toprovide compound (3). In step C, the substituent R⁴ is introduced with apalladium coupling, using a suitable functionalized aryl or heteroarylsystem, for example an aryl triflate, in the presence of a palladiumcatalyst such as Pd₂DBA₃/Xantphos in a solvent such as toluene with abase such as sodium tert-butoxide to provide compound (4). In step D,the protecting group of ring X compound (4) is removed, for examplehydrogenolysis by Pd/C in the presence of H₂ in a polar solvent such asEtOH/THF to provide compound (5). In the final step, E, R¹ is introducedto provide a compound of Formula I, for example by treating with an acidchloride having the formula Cl—C(O)C(R^(A))

C(R^(B))_(p) or Cl—SO₂C(R^(A))

C(R^(B))_(p), or an anhydride having the formula C(R^(B))_(p)

C(R^(A))C(R^(A))C(O)OC(O)C(R^(A))

C(R^(B))_(p), where R^(A), R^(B) and p are as defined for Formula I. Forexample, in the case where R¹ is an acryloyl group, this reactionproceeds, for example, in a solvent such as methylene chloride in thepresence of acryloyl chloride or an acryloyl anhydride and a base suchas Hunig's base. In some cases, the species R⁴ will also contain aprotecting group, which can be removed at a subsequent step in thesynthetic sequence.

Compounds (1), (2), (3), (4) and (5) as shown and described above forScheme I are useful as intermediates for preparing compounds of FormulaI and are provided as further aspects of the invention.

Compounds of Formula I wherein L is a bond, —Y—R² is other than hydrogenand R⁴ is aryl or heteroaryl can be prepared according to Scheme II. Instep A, an appropriately functionalized dihydropyridopyrimidine (6) iscoupled to a heterocycle containing one nucleophilic amine species, withthe other bound to a protecting group to provide compound (7). Thiscoupling proceeds in a solvent such as dichloromethane in the presenceof a base such as triethylamine or Hunig's base. In step B, thesubstituent —Y—R² is introduced by substitution of the chlorine by anucleophile, for example (S)-1-(dimethylamino-propan-2-ol in a polarsolvent such as dioxane to provide compound (8). In step C, the Bocgroup is removed using conditions known in the art, for example withtrifluoroacetic acid in a solvent such as dichloromethane to providecompound (9). In step D, the substituent R⁴ is introduced with apalladium coupling, using a suitable functionalized aryl or heteroarylsystem, for example an aryl triflate, in the presence of a palladiumcatalyst such as Pd₂DBA₃/BINAP in a solvent such as toluene with a basesuch as sodium tert-butoxide to provide compound (10). In step E, theprotecting group of ring X is removed, for example hydrogenolysis byPd/C in the presence of H₂ in a polar solvent such as EtOH/THF toprovide compound (11). In step F, R¹ is introduced to provide a compoundof Formula I, for example by treating with an acid chloride having theformula Cl—C(O)C(R^(A))

C(R^(B))_(p) or Cl—SO₂C(R^(A))

C(R^(B))_(p), or an anhydride having the formula C(R^(B))_(p)

C(R^(A))C(O)OC(O)C(R^(A))

C(R^(B))_(p), where R^(A), R^(B) and p are as defined for Formula I. Forexample, in the case where R¹ is an acryloyl group, this reactionproceeds, for example, in a solvent such as methylene chloride in thepresence of acryloyl chloride acryloyl anhydride and a base such asHunig's base. In some cases, the species R⁴ and R² may also containprotecting groups, which can be removed at a subsequent step in thesynthetic sequence.

Compounds (6), (7), (8), (9), (10) and (11) as shown and described abovefor Scheme 2 are useful as intermediates for preparing compounds ofFormula I, Formula I-A or Formula I-B and are provided as furtheraspects of the invention.

Accordingly, also provide is a process for preparing a compound ofFormula I, comprising:

-   -   (a) for a compound of Formula I where Y is a bond and R² is        hydrogen, reacting a compound of formula 5

-   -   where X, R³ and R⁴ are as defined for Formula I, with an acid        chloride having the formula Cl—C(O)C(R^(A))        C(R^(B))_(p) or Cl—SO₂C(R^(A))        C(R^(B))_(p) or an anhydride having the formula C(R^(B))_(p)        C(R^(A))C(O)C(O)C(R^(A))        C(R^(B))_(p), where R^(A), R^(B) and p are as defined for        Formula I, in the presence of a base; or    -   (b) for a compound of Formula I wherein L is a bond and —Y—R² is        other than hydrogen, reacting a compound of formula (11)

-   -   wherein L is a bond, —Y—R² is other than hydrogen, and X, R³ and        R⁴ are as defined for Formula I, with an acid chloride having        the formula Cl—C(O)C(R^(A))        C(R^(B))_(p) or Cl—SO₂C(R^(A))        C(R^(B))_(p), or an anhydride having the formula C(R^(B))_(p)        C(R^(A))C(O)OC(O)C(R^(A))        C(R^(B))_(p), where R^(A), R^(B) and p are as defined for        Formula I, in the presence of a base; and    -   optionally forming a salt thereof.

The compounds of the present invention may have one or more chiralcenter and may be synthesized as stereoisomeric mixtures, isomers ofidentical constitution that differ in the arrangement of their atoms inspace. The compounds may be used as mixtures or the individualcomponents/isomers may be separated using commercially availablereagents and conventional methods for isolation of stereoisomers andenantiomers well-known to those skilled in the art, e.g., usingCHIRALPAK® (Sigma-Aldrich) or CHIRALCEL® (Diacel Corp) chiralchromatographic HPLC columns according to the manufacturer'sinstructions. Alternatively, compounds of the present invention may besynthesized using optically pure, chiral reagents and intermediates toprepare individual isomers or enantiomers. Unless otherwise indicated,all chiral (enantiomeric and diastereomeric) and racemic forms arewithin the scope of the invention. Unless otherwise indicated, wheneverthe specification, including the claims, refers to compounds of theinvention, the term “compound” is to be understood to encompass allchiral (enantiomeric and diastereomeric) and racemic forms.

The following Examples are intended to illustrate further certainembodiments of the invention and are not intended to limit the scope ofthe invention.

Intermediate 1

3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate

3-Hydroxynaphthalen-1-yl trifluoromethanesulfonate (13.101 g, 44.831mmol) was dissolved in dichloromethane (100 mL) and stirred at 0° C. Tothis solution was added chloro(methoxy)methane (3.7456 ml, 49.315 mmol)and Hunig's base (11.745 mL, 67.247 mmol). The reaction was stirred at0° C. for 4 hrs. The reaction was partitioned with 1M HCl and washedwith saturated sodium bicarbonate. The combined organic layers weredried over magnesium sulfate and concentrated under vacuum. Theconcentrated material was loaded onto a 120 g RediSep® gold silica gelcolumn with dichloromethane and purified by normal phase chromatography(CombiFlash®, 0%-20% ethyl acetate/hexanes as the eluent) to give3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (11.785 g,35.045 mmol, 78.171% yield).

Intermediate 2

2-bromo-7-(methoxymethoxy)naphthalene

To a solution of 7-bromonaphthalen-2-ol (2.0 g, 9.0 mmol) in dimethylacetamide (40 mL) was added chloro(methoxy)methane (1.4 g, 18 mmol) andcesium carbonate (5.8 g, 18 mmol) and the reaction mixture was stirredovernight at room temperature. The reaction was diluted with water andthe aqueous layer washed with ethyl acetate. The combined organic layerswere washed with water and brine, dried over magnesium sulfate andconcentrated under vacuum. The crude material was purified by normalphase chromatography using 5-50% ethyl acetate/hexanes as the eluent togive 2-bromo-7-(methoxymethoxy)naphthalene (1.0 g, 3.7 mmol, 42% yield).

Intermediate 3

2-bromo-1-fluoro-3-(methoxymethyl)benzene

To a stirred solution of 2-bromo-3-fluorophenol (1422 mg, 7.445 mmol) in22 mL tetrahydrofuran at room temperature under nitrogen was added NaH(327.6 mg, 8.190 mmol) neat as a solid portion wise. After 15 minutes, asolution had formed. Chloro(methoxy)methane (678.6 μL, 8.934 mmol) wasadded by syringe. After stirring for 2 hours, the reaction was quenchedwith saturated ammonium chloride solution and then partitioned betweenethyl acetate (30 mL) and water (30 mL). The combined organic layerswere isolated, washed with brine, dried over MgSO₄, filtered andconcentrated. The crude product was loaded in a minimum ofdichloromethane onto a 40 gram RediSep® column pre-wet with hexanes andeluted with an ethyl acetate/hexanes gradient (0% to 20% ethyl acetate).Fractions containing the product were combined and concentrated toprovide the product as a clear oil (1.45 g, 83%).

Intermediate 4

2-bromo-1-fluoro-4-(methoxymethoxy)benzene

To a stirred solution of 3-bromo-4-fluorophenol (327 mg, 1.71 mmol) in5.1 mL tetrahydrofuran at room temperature under nitrogen was added NaH(75.3 mg, 1.88 mmol) neat as a solid portion wise. After 15 minutes, asolution had formed. Chloro(methoxy)methane (156 μL, 2.05 mmol) wasadded by syringe. After stirring for 2 hours, the reaction was quenchedwith saturated ammonium chloride solution and partitioned between ethylacetate and water. The combined organic layers were washed with brine,dried over MgSO₄, filtered and concentrated. The crude product wasloaded in a minimum of dichloromethane onto a 24 gram RediSep® columnpre-wet with hexanes and eluted with an ethyl acetate/hexanes gradient(0% to 20% ethyl acetate). Fractions containing the product werecombined and concentrated to provide the product as a clear oil (120 mg,29.8%)

Intermediate 5

4-bromo-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

To a solution of 4-bromo-5-methyl-1H-indazole (0.7 g, 3.3 mmol) indimethyl acetamide (30 mL) cooled to 0° C. was added NaH (0.19 g, 4.6mmol) in portions and the reaction mixture was purged with nitrogen. Thereaction was stirred for 20 minutes, and then(2-(chloromethoxy)ethyl)trimethylsilane (0.83 g, 5.0 mmol) was added andthe reaction was stirred for 2 hours while warming to room temperature.The reaction was quenched by pouring into water and the aqueous layerwas extracted into ethyl acetate. The combined organic layers werewashed with water and brine, dried over MgSO₄ and concentrated undervacuum. The crude material was purified by chromatography using 10-50%ethyl acetate/hexanes as the eluent to give4-bromo-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (0.87g, 79%).

Intermediate 6

(R)-1-(pyrrolidin-1-yl)propan-2-ol

In a sealed tube, R-(+)-Propylene oxide (3.69 mL, 52.7 mmol) was cooledto −78° C. and then sparged with anhydrous dimethyl amine for a fewminutes. The reaction mixture was heated to 70° C. for 16 hours. Thereaction was cooled and concentrated in vacuo for 20 minutes to provide(R)-1-(pyrrolidin-1-yl)propan-2-ol (5.35 g, 41.4 mmol, 98.2% yield).

Intermediate 7

(R)-1-morpholinopropan-2-ol

In a sealed tube, R-(+)-Propylene oxide (2.111 mL, 30.13 mmol) andmorpholine (1.490 mL, 17.22 mmol) were heated to 70° C. for 20 hours.The reaction was cooled and concentrated in vacuo to provide(R)-1-morpholinopropan-2-ol (2.47 g, 17.01 mmol, 98.80% yield).

Intermediate 8

(R)-1-(dimethylamino)butan-2-ol

In a sealed tube, R-(+)-Propylene oxide (4.00 g, 55.5 mmol) anddimethylamine (1.00 g, 22.2 mmol), were heated to 65° C. for 18 hours.The reaction was cooled and concentrated in vacuo. The resulting residuewas purified by silica gel (0-12% MeOH in DCM) to provide(R)-1-(dimethylamino)butan-2-ol (1.38 g, 11.8 mmol, 53.1% yield).

Intermediate 9

(R)-1-((R)-3-methoxypyrrolidin-1-yl)propan-2-ol

In a sealed tube, (R)-3-methoxypyrrolidine hydrochloride (1.00 g, 7.27mmol), TEA (2.03 mL, 14.5 mmol) and R-(+)-Propylene oxide (1.27 mL, 18.2mmol) were heated to 65° C. for 18 hours. The reaction was cooled andconcentrated in vacuo. The resulting residue was purified by silica gel(0-12% MeOH in DCM) to provide(R)-1-((R)-3-methoxypyrrolidin-1-yl)propan-2-ol (775 mg, 4.87 mmol,67.0% yield).

Intermediate 10

(R)-1-((S)-3-methoxypyrrolidin-1-yl)propan-2-ol

In a sealed tube, (S)-3-methoxypyrrolidine hydrochloride (1.00 g, 7.27mmol), TEA (2.03 mL, 14.5 mmol) and R-(+)-Propylene oxide (1.27 mL, 18.2mmol) were heated to 65° C. for 18 hours. The reaction was cooled andconcentrated in vacuo. The resulting residue was purified by silica gel(0-12% MeOH in DCM) to provide(R)-1-((S)-3-methoxypyrrolidin-1-yl)propan-2-ol (781 mg, 4.90 mmol,67.5% yield).

Intermediate 11

(R)-1-((S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)propan-2-ol

In a sealed tube, R-(+)-Propylene oxide (0.609 mL, 8.69 mmol) and(S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidine (1.00 g, 4.97 mmol) wereheated to 70° C. for 20 hours. The reaction was cooled and concentratedin vacuo to provide(R)-1-((S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)propan-2-ol(1.29 g, 4.20 mmol, 84.6% yield).

Intermediate 12

tert-butyl 2-(hydroxymethyl)-4-methylpiperazine-1-carboxylate

To a suspension of lithium chloride (246 mg, 5.81 mmol) and LithiumBorohydride (126 mg, 5.81 mmol) in ethanol (9 mL), at 0° C. undernitrogen, a solution of 1-(tert-butyl) 2-methyl4-methylpiperazine-1,2-dicarboxylate (750 mg, 2.90 mmol) in dry THF (6mL) was added dropwise. The reaction was stirred overnight forming awhite precipitate. The precipitate was filtered and washed with ethanol.The combined filtrate and organic extracts were concentrated to providea white residue which was extracted with ethyl acetate. The combinedorganic layers were washed with saturated sodium chloride solution,dried over sodium sulfate and concentrated in vacuo. The residue waspurified by chromatography with isocratic 10% MeOH in DCM with 0.2%NH₄OH to provide tert-butyl2-(hydroxymethyl)-4-methylpiperazine-1-carboxylate (104 mg, 0.452 mmol,15.6% yield).

Intermediate 13

(S)-2-(2-methylpiperidin-1-yl)ethan-1-ol

A mixture of (S)-2-methylpiperidine (100 mg, 1.01 mmol), 2-bromoethanol(78 μL, 139 mg, 1.11 mmol, 1.1 eq.), sodium iodide (151 mg, 1 eq.),potassium carbonate (418 mg, 3 eq.) and acetonitrile (1 mL) in a 4-mLvial was purged with nitrogen, sealed and stirred at room temperaturefor 2 days. The reaction mixture was partitioned between diethyl ether(15 mL) and water (2 mL). The ether layer was washed with brine (2 mL),acidified with TFA and dried under high vacuum for 2 days. The residuewas washed with ether (3 mL), diluted with water (0.5 mL) and basifiedwith 10M NaOH (0.2 mL). The layers were separated and the upper layerwas carefully dried over NaOH. The ether solution was evaporated undernitrogen to yield crude (S)-2-(2-methylpiperidin-1-yl)ethan-1-ol (100mg, 0.698 mmol, 69.24% yield) as colorless oil.

Intermediate 14

(R)-2-(2-methylpiperidin-1-yl)ethan-1-ol

Synthesized according to the method of Intermediate 13, using(R)-2-methylpiperidine (99 mg, 1 mmol) in place of(S)-2-methylpiperidine.

Intermediate 15

(S)-2-(3-methoxypiperidin-1-yl)ethan-1-ol

Synthesized according to the method of Intermediate 13, using(S)-3-methoxypiperidine (173 mg, 1.50 mmol) in place of(S)-2-methylpiperidine.

Intermediate 16

(R)-2-(3-methoxypiperidin-1-yl)ethan-1-ol

Synthesized according to the method of Intermediate 13, usingR-3-methoxypiperidine (173 mg, 1.50 mmol) in place of(S)-2-methylpiperidine.

Intermediate 17

3-(1,4-oxazepan-4-yl)propan-1-ol

To a vial was added homomorpholine (0.250 g, 2.472 mmol), Acetonitrile(4.943 mL, 2.472 mmol) and 3-Bromo-1-propanol (0.2459 mL, 2.719 mmol).Potassium carbonate (0.6832 g, 4.943 mmol) was added and the mixture waswarmed to 50° C. and stirred for 6 hours. The mixture was cooled toambient temperature, diluted with DCM, filtered and the collected solidswere washed with DCM. The filtrate was concentrated in vacuo and thecrude oil was purified via column chromatography (Biotage Isolera, 12 gIsco RediSep Gold, 10-20% MeOH/DCM with 0.2% N₄OH) to afford3-(1,4-oxazepan-4-yl)propan-1-ol (0.272 g, 1.708 mmol) as a colorlessoil.

Intermediate 18

3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propan-1-ol

Synthesized according to the method of Intermediate 17, using(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptane (0.250 g, 2.522 mmol) in placeof homomorpholine.

Intermediate 19

2-(4-methoxypiperidin-1-yl)ethan-1-ol

Synthesized according to the method of Intermediate 13, using4-methoxypiperidine (173 mg, 1.50 mmol) in place of(S)-2-methylpiperidine.

Intermediate 20

2-(4,4-difluoropiperidin-1-yl)ethan-1-ol

Synthesized according to the method of Intermediate 13, using4,4-difluoropiperidine hydrochloride (173 mg, 1.50 mmol) in place of(S)-2-methylpiperidine.

Intermediate 21

(S)-2-(3-fluoropiperidin-1-yl)ethan-1-ol

Synthesized according to the method of Intermediate 13, usingS-3-fluoropiperidine hydrochloride (209 mg, 1.50 mmol) in place of(S)-2-methylpiperidine.

Intermediate 22

benzyl4-(7-(3-(benzyloxy)naphthalen-1-yl)-2-(methylsulfinyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

Step A: tert-butyl4-hydroxy-2-(methylthio)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:To a stirred solution of 1-tert-butyl 4-ethyl3-oxopiperidine-1,4-dicarboxylate (50.0 g, 184 mmol, 1.00 eq) in MeOH(1.00 L) at 25° C. under nitrogen was added NaOMe (49.8 g, 921 mmol,5.00 eq), followed by 2-methylisothiourea (62.4 g, 331 mmol, 1.80 eq,H₂SO₄) as a solid. The reaction mixture was stirred at 25° C. for 16hours. The reaction mixture was adjusted to pH 5 with HCl (2 M), and themixture was concentrated under reduced pressure to removed MeOH. Theresidue was suspended in 300 mL of ethyl acetate and 300 mL of water andstirred rapidly. The suspension was filtered and the white solid wascollected. The filtrate was separated and the organic layer was washedwith water (1×300 mL) and brine (1×200 mL). The combined organic layerswere isolated, dried over Na₂SO₄, filtered and concentrated to providetert-butyl4-hydroxy-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(51.0 g, 138 mmol, 75.4% yield, 81.0% purity) as a white solid which asused directly in the next step without further purification. ESI MS m/z298.2 [M+H]⁺.

Step B: tert-butyl2-methylsulfanyl-4-(trifluoromethylsulfonyloxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate:To a stirred suspension of tert-butyl4-hydroxy-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(51.0 g, 171 mmol, 1.00 eq) in DCM (500 mL) at 0° C. was added DIEA(44.3 g, 343 mmol, 59.9 mL, 2.00 eq), followed bytrifluoromethanesulfonic anhydride (72.6 g, 257 mmol, 42.4 mL, 1.50 eq)under nitrogen. Immediately a brown solution formed. After stirring at25° C. for 16 hours, the reaction was concentrated to give a brown oil.The brown oil was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=1:0 to 10:1) to provide tert-butyl2-methylsulfanyl-4-(trifluoromethylsulfonyloxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(46.0 g, 107 mmol, 62.4% yield) as a yellow solid ESI MS m/z 430.2[M+H]⁺.

Step C: tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate:To a stirred solution of tert-butyl2-methylsulfanyl-4-(trifluoromethylsulfonyloxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(46.0 g, 107 mmol, 1.00 eq) in DMF (500 mL) was added DIEA (27.7 g, 214mmol, 37.4 mL, 2.00 eq) followed by benzyl piperazine-1-carboxylate(25.9 g, 117 mmol, 22.7 mL, 1.10 eq). The reaction was heated to 100° C.for 1 hour under a nitrogen atmosphere. The reaction mixture was pouredinto ethyl acetate (300 mL), washed with H₂O (300 mL×3) and brine (200mL), dried over anhydrous Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=1:0 to 5:1) to give tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(51.0 g, 96.9 mmol, 90.5% yield, 92.0% purity) as a white solid ESI MSm/z 500.3 [M+H]⁺.

Step D: Benzyl4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate: To a solution of tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(25.0 g, 50.0 mmol, 1.00 eq) in DCM (50.0 mL) was added TFA (85.6 g, 750mmol, 55.6 mL, 15.0 eq). After stirring at 25° C. for 1 hour, thereaction mixture was concentrated under reduced pressure. The residuewas dissolved in 300 mL of ethyl acetate and 300 mL of water and stirredrapidly. The mixture was adjusted to pH 8 with Na₂CO₃. The organic layerwas washed with water (1×300 mL) and brine (1×200 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to providebenzyl4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (19.0 g, 46.6 mmol, 93.2% yield, 98.0% purity)as a yellow oil. ESI MS m/z 400.2 [M+H]⁺.

Step E: Benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:A mixture of 3-benzyloxy-1-bromo-naphthalene (16.3 g, 52.1 mmol, 1.30eq), benzyl4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(16.0 g, 40.1 mmol, 1.00 eq), Cs₂CO₃ (32.6 g, 100 mmol, 2.50 eq),Pd₂(dba)₃ (5.50 g, 6.01 mmol, 0.15 eq) and2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos) (3.74 g,8.01 mmol, 0.20 eq) in dioxane (300 mL) was degassed and purged withnitrogen 3 times. The mixture was stirred at 85° C. for 5 hours under anitrogen atmosphere. The reaction mixture was quenched by adding water(200 mL) at 0° C., and extracted with ethyl acetate (3×200 mL). Thecombined organic layers were washed with brine (3×150 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by column chromatography (SiO₂, DCM/MeOH=10/1 to 5/1) toprovide benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(16.0 g, 22.8 mmol, 56.9% yield, 90.0% purity) as a yellow solid. ESI MSm/z 632.5 [M+H]⁺.

Step F: Benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate: To a stirred solution ofbenzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(8.00 g, 12.7 mmol, 1.00 eq) in DCM (200 mL) was added m-CPBA (2.73 g,12.7 mmol, 80.0% purity, 1.00 eq) at 0° C. under nitrogen. Afterstirring at 0° C. for 2 hours under a nitrogen atmosphere, the reactionmixture was quenched by adding Na₂S₂O₃ (10.0 mL) at 0° C., diluted withwater (100 mL) and extracted with DCM (200 mL). The combined organiclayers were washed with brine (200 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by column chromatography (SiO₂, DCM/MeOH=1/0 to 10/1) toprovide benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate (3.50 g, 4.92 mmol, 38.8%yield, 91.0% purity) as a yellow solid. ESI MS m/z 648.5 [M+H]⁺.

Intermediate 23

(R)-1-(4-(2-hydroxypropyl)piperazin-1-yl)ethan-1-one

Step A: 1-[4-[(2R)-2-hydroxypropyl]piperazin-1-yl]ethanone:(2R)-2-methyloxirane (1.00 g, 17.2 mmol, 1.20 mL, 1.00 eq) and1-piperazin-1-ylethanone (8.00 g, 62.4 mmol, 3.62 eq) were taken up intoa microwave tube. The sealed tube was heated at 150° C. for 1 hour undermicrowave. The mixture was dissolved in DCM (80.0 mL), added (Boc)₂O(3.62 eq, 13.6 g) and stirred at 20° C. for 1 hour. The residue waspurified by column chromatography (DCM/MeOH 100/1 to 10/1) to give1-[4-[(2R)-2-hydroxypropyl]piperazin-1-yl]ethanone (3.80 g, 13.5 mmol,78.2% yield, 66.0% purity) as a yellow oil.

Intermediate 24

1-(benzyloxy)-3-bromo-5-cyclopropylbenzene

Step A: 1-benzyloxy-3,5-dibromo-benzene: To a mixture of3,5-dibromophenol (1.50 g, 5.95 mmol, 1.00 eq) and K₂CO₃ (2.47 g, 17.9mmol, 3.00 eq) in MeCN (30.0 mL) was added benzyl bromide (1.07 g, 6.25mmol, 742 μL, 1.05 eq), the reaction mixture was stirred at 80° C. for 2hours. The reaction mixture was filtered and concentrated. The residuewas purified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=1:1 to give 1-benzyloxy-3,5-dibromobenzene (1.60 g, 4.68 mmol,78.6% yield) as colorless oil.

Step B: 1-benzyloxy-3-bromo-5-cyclopropylbenzene: To a mixture of1-benzyloxy-3,5-dibromobenzene (1.20 g, 3.51 mmol, 1.00 eq) andcyclopropylboronic acid (392 mg, 4.56 mmol, 1.30 eq) in H₂O (4.00 mL)and dioxane (20.0 mL) was added Pd(dppf)Cl₂ (513 mg, 702 μmol, 0.20 eq)and Cs₂CO₃ (2.29 g, 7.02 mmol, 2.00 eq). The reaction mixture wasstirred at 90° C. for 12 hours under N₂. The reaction mixture was addedto water (20 mL) and extracted with ethyl acetate (2×15 mL). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=1:1 to give1-benzyloxy-3-bromo-5-cyclopropyl-benzene (270 mg, 890 μmol, 25.4%yield) as colorless oil.

Intermediate 25

benzyl4-(2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

Step A: tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate:To a mixture of 3-morpholinopropan-1-ol (5.46 g, 37.6 mmol, 2.00 eq) inTHF (100 mL) was added NaH (2.26 g, 56.4 mmol, 60.0% purity, 3.00 eq) inportions at 0° C. After the mixture was stirred at 0° C. for 0.5 hour, asolution of tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-methylsulfonyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(10.0 g, 18.8 mmol, 1.00 eq) in THF (100 mL) was added, and the reactionmixture was stirred at 0° C. for 1.5 hours under N₂. The mixture waspoured into NH₄Cl aqueous (300 mL), and extracted with DCM (2×200 mL).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=50:1 to 10:1) to give tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(7.70 g, 12.8 mmol, 67.8% yield, 98.8% purity) as a yellow oil. ESI MSm/z 597.4 [M+H]⁺.

Step B: benzyl4-[2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a mixture of tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(7.70 g, 12.9 mmol, 1.00 eq) in DCM (80.0 mL) was added TFA (119 g, 1.04mol, 76.9 mL, 80.6 eq), and the reaction mixture was stirred at 15° C.for 1 hour. The reaction mixture was concentrated, then diluted with DCM(100 mL) and adjusted to pH 8 with aqueous NaOH. The organic layer wasseparated, dried over Na₂SO₄, filtered and concentrated to give benzyl4-[2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(6.00 g, 11.2 mmol, 86.9% yield, 92.8% purity) as yellow oil. ESI MS m/z497.4 [M+H]⁺.

Intermediate 26

4-(benzyloxy)-2-bromo-1-fluorobenzene

To a solution of 3-bromo-4-fluorophenol (4.00 g, 20.9 mmol, 1.00 eq) andK₂CO₃ (8.68 g, 62.8 mmol, 3.00 eq) in ACN (80.0 mL) was added benzylbromide (3.65 g, 21.4 mmol, 2.54 mL, 1.02 eq) and the reaction mixturewas stirred at 60° C. for 2 hrs. The reaction mixture was filtered andconcentrated in vacuum. The residue was purified by silica gelchromatography (petroleum ether:ethyl acetate; gradient from 1:0 to10:1) to give 4-benzyloxy-2-bromo-1-fluoro-benzene (5.02 g, 17.0 mmol,81.0% yield, 95% purity) was obtained as white solid.

Intermediate 27

2-(3-fluoropyrrolidin-1-yl)ethan-1-ol

Step A: tert-butyl 3-fluoropyrrolidine-1-carboxylate: To a solution oftert-butyl 3-hydroxypyrrolidine-1-carboxylate (10.0 g, 53.4 mmol, 1.00eq) in DCM (150.00 mL) was added diethylaminosulfur trifluoride (DAST)(12.9 g, 80.1 mmol, 10.6 mL, 1.50 eq) at −40° C. under a nitrogenatmosphere. After stirring at −40° C. for 2 hours, the mixture waswarmed to 20° C. and stirred for 16 hours. The mixture was poured into5% aqueous sodium bicarbonate (200 mL) and extracted withdichloromethane (2×100 mL). The organic layer was dried over sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography over silica gel (petroleum ether/ethylacetate 100:1 to 5:1). The desired fractions were collected andconcentrated under vacuum to give tert-butyl3-fluoropyrrolidine-1-carboxylate (4.30 g, 22.7 mmol, 42.6% yield) as acolorless oil. ¹H NMR (400 MHz, Chloroform-d) δ=5.27 (t, J=3.6 Hz,0.5H), 5.13 (t, J=3.6 Hz, 0.5H), 3.77-3.38 (m, 4H), 2.26-2.15 (m, 1H),2.08-1.85 (m, 1H), 1.46 (s, 9H).

Step B: 3-fluoropyrrolidine: To a solution of tert-butyl3-fluoropyrrolidine-1-carboxylate (4.30 g, 22.7 mmol, 1.00 eq) in DCM(50.00 mL) was added HCl/dioxane (4 M, 35.0 mL, 6.16 eq) dropwise at 0°C. The mixture was warmed to 20° C. and stirred for 1 hour. The mixturewas concentrated under vacuum. The residue was triturated withdiisopropyl ether (20 mL) and the precipitate was filtered and driedunder vacuum to provide 3-fluoropyrrolidine (2.70 g, 21.5 mmol, 94.6%yield, HCl) as a white solid. ¹H NMR (400 MHz, Methanol-d₄) δ=5.51 (t,J=3.6 Hz, 0.5H), 5.38 (t, J=3.6 Hz, 1H), 3.66-3.27 (m, 5H), 2.45-2.12(m, 2H).

Step C: methyl 2-(3-fluoropyrrolidin-1-yl)acetate: A suspension of3-fluoropyrrolidine (2.70 g, 21.5 mmol, 1.00 eq, HCl) in DCM (27.00 mL)was cooled to 0° C. Triethylamine (5.44 g, 53.8 mmol, 7.45 mL, 2.50 eq)and methyl 2-bromoacetate (3.62 g, 23.7 mmol, 2.23 mL, 1.10 eq) wereadded and the reaction mixture was stirred at 20° C. for 16 h. Thereaction mixture was diluted with CH₂Cl₂ (100 mL) and water (50 mL). Theorganic layer was washed with 5% aqueous citric acid solution (1×50 mL).The water layer was basified by saturated aqueous sodium carbonatesolution (20 mL) and extracted with ethyl acetate (3×100 mL). Thecombined organic layers were dried over sodium sulfate and concentratedin vacuo to give methyl 2-(3-fluoropyrrolidin-1-yl)acetate (2.20 g, 13.7mmol, 63.5% yield). ¹H NMR (400 MHz, Chloroform-d) δ=5.22-5.02 (m, 1H),3.66 (s, 3H), 3.35 (s, 2H), 3.07-2.93 (m, 1H), 2.91-2.77 (m, 2H), 2.67(dt, J=5.2, 8.4 Hz, 1H), 2.21-1.93 (m, 2H).

Step D: 2-(3-fluoropyrrolidin-1-yl)ethanol: To a solution of LiAlH₄ (706mg, 18.6 mmol, 1.50 eq) in THF (20 mL) was added a solution of methyl2-(3-fluoropyrrolidin-1-yl)acetate (2.00 g, 12.4 mmol, 1.00 eq) in THF(10 mL) dropwise at 0° C. The mixture was warmed up to 20° C. andstirred for 3 hours. The mixture was quenched with saturated aqueoussodium sulfate solution (1 mL). The mixture was filtered and thefiltrate was concentrated under vacuum. The product was purified bysilica gel chromatography using 5% MeOH in DMC. The desired fractionswere collected and concentrated under vacuum to give2-(3-fluoropyrrolidin-1-yl)ethanol (1.20 g, 9.01 mmol, 72.6% yield) as acolorless oil. ¹H NMR (400 MHz, Chloroform-d) δ=5.28-5.05 (m, 1H),3.68-3.61 (m, 2H), 2.99-2.73 (m, 4H), 2.72-2.67 (m, 2H), 2.58-2.45 (m,1H), 2.28-1.97 (m, 2H).

Intermediate 28

1-(tert-butyl) 3-methyl piperazine-1,3-dicarboxylate

Step A: methyl piperazine-2-carboxylate: To a mixture of 1-tert-butyl2-methyl piperazine-1,2-dicarboxylate (5.0 g, 22.6 mmol, 1.00 eq) inMeOH (50.0 mL) was added HCl/dioxane (4.0 M, 134 mL). The reactionmixture was degassed and purged with nitrogen 3 times, and the mixturewas stirred at 25° C. for 12 hours under a nitrogen atmosphere. Thereaction mixture was concentrated under reduced pressure to dryness togive methyl piperazine-2-carboxylate (4.89 g, 2HCl, crude) as a whitesolid, which was used directly in the next step without furtherpurification.

Step B: 1-(tert-butyl) 3-methyl piperazine-1,3-dicarboxylate: To asolution of methyl piperazine-2-carboxylate (4.30 g, crude) and TEA(8.02 g, 79.2 mmol, 11.0 mL) in MeOH (50.0 mL) was added di-tert-butyldicarbonate (4.32 g, 19.8 mmol, 4.55 mL). After stirring at 25° C. for12 hours, the reaction mixture was filtered and concentrated underreduced pressure to dryness. The residue was purified by columnchromatography (SiO₂, DCM/MeOH=1:0 to 20:1) to give 1-(tert-butyl)3-methyl piperazine-1,3-dicarboxylate (4.80 g, 19.7 mmol, two steps,99.0% yield) as a colorless oil. ¹H NMR (400 MHz, chloroform-d)δ=4.10-3.85 (m, 1H), 3.73 (s, 3H), 3.71-3.65 (m, 1H), 3.47-3.38 (m, 1H),3.10-2.98 (m, 2H), 2.78-2.66 (m, 1H), 2.17 (s, 1H), 1.46 (s, 9H).

Intermediate 29

4-bromonaphthalen-2-ol

Step A: 2,4-dibromonaphthalen-1-amine: To a solution of Br₂ (246 g, 1.54mol, 79.3 mL, 2.18 eq) in AcOH (750 mL) was added a solution ofnaphthalen-1-amine (101 g, 705 mmol, 99.0 mL, 1.00 eq) in AcOH (500 mL)at ambient temperature, and the reaction was stirred at 70° C. for 1hour. The reaction mixture was cooled at room temperature and filtered.The filter cake was washed with AcOH (300 mL), then added to 20% aqueousof NaOH (1.2 L). The mixture was stirred for 20 min and filtered. Theisolated solid was washed with water (1 L) and dried under vacuum toprovide 2,4-dibromonaphthalen-1-amine (200 g, 664 mmol, 94.2% yield) asgray solid. ESI MS m/z 301.9 [M+H]⁺.

Step B: 4-bromo-1-diazonio-naphthalen-2-olate: To a solution of2,4-dibromonaphthalen-1-amine (60.0 g, 199 mmol, 1.00 eq) in AcOH (900mL) and propionic acid (50 mL) was added NaNO₂ (16.5 g, 239 mmol, 13.0mL, 1.20 eq) portionwise at 5-8° C. over 30 min, and then the reactionmixture was stirred at 5-8° C. for 30 min. The reaction mixture waspoured into ice-water (4000 mL), and the resulting solid was collectedand washed with water (2×50 mL) to provide4-bromo-1-diazonio-naphthalen-2-olate (150 g, wet crude) as gray solidwhich was used directly in the next step ¹H NMR (400 MHz, CDCl₃) δ8.12-8.10 (d, J=8.4 Hz, 1H), 7.62-7.58 (t, J=7.6 Hz, 1H), 7.41-7.37 (t,J=7.6 Hz, 1H), 7.31-7.29 (d, J=8.0 Hz, 1H), 7.20 (s, 1H).

Step C: 4-bromonaphthalen-2-ol: To a solution of4-bromo-1-diazonio-naphthalen-2-olate (100 g, 402 mmol, 1.00 eq) in EtOH(2.00 L) was added portionwise NaBH₄ (30.4 g, 803 mmol, 2.00 eq) at13-15° C. over 1 h, and the reaction mixture was stirred at 15-18° C.for 3 hrs. The reaction was filtered and concentrated to dryness. Theresidue was dissolved in DCM (1000 mL) and washed with water (500 mL×2).The organic phase was dried over Na₂SO₄ and concentrated to dryness. Theresidue was purified by silica gel column chromatograph, eluting withdiethyl ether/ethyl acetate (60:1 to 10:1). The isolated product wasfurther purified by reversed phase HPLC to provide4-bromonaphthalen-2-ol (40.0 g, 139 mmol, 17.3% yield, 77.4% purity) asa gray solid. ¹H NMR (400 MHz, CDCl₃) δ 8.07-8.05 (d, J=8.0 Hz, 1H),7.60-7.58 (d, J=7.6 Hz, 1H), 7.41-7.36 (m, 3H), 7.07 (s, 1H).

Step D: 3-benzyloxy-1-bromo-naphthalene: A mixture of4-bromonaphthalen-2-ol (30.0 g, 134 mmol, 1.00 eq), benzyl bromide (25.3g, 148 mmol, 17.6 mL, 1.10 eq) and K₂CO₃ (55.7 g, 403 mmol, 3.00 eq) inMeCN (500 mL) was heated at 80° C. for 1 hr. The reaction mixture wasfiltered and concentrated to dryness. The residue was purified by silicagel column chromatography, eluting with diethyl ether/ethyl acetate(100:1 to 60:1) to provide 3-benzyloxy-1-bromo-naphthalene (40.0 g, 128mmol, 95% yield) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.19-8.17 (d,J=8.0 Hz, 1H), 7.75-7.32 (d, J=8.8 Hz, 1H), 7.64-7.63 (d, J=2.4 Hz, 1H),7.52-7.37 (m, 7H), 7.23-7.21 (d, J=2.0 Hz, 1H), 5.2 (s, 2H).

Intermediate 30

3-methoxynaphthalen-1-yl trifluoromethanesulfonate

Step A: 3-methoxynaphthalen-1-ol: To a solution of naphthalene-1,3-diol(3.00 g, 18.7 mmol, 1.00 eq) in MeOH (60.0 mL) was added HCl/MeOH (4 M,60.0 mL, 12.8 eq) at 0° C. The mixture was stirred at 25° C. for 60hours. The solvent was removed under vacuum. The residue was purified bysilica gel chromatogmphy (diethyl ether:ethyl acetate=10:1 to 5:1) togive 3-methoxynaphthalen-1-ol (2.10 g, 12.1 mmol, 64.4% yield) as abrown solid. ¹H NMR (400 MHz, CDCl₃-d₆) δ=8.10-8.08 (d, J=8.4 Hz, 1H),7.73-7.71 (d, J=8.4 Hz, 1H), 7.47-7.45 (m, 1H), 7.38-7.35 (m, 1H),6.80-6.79 (d, J=2.0 Hz, 1H), 6.56-6.55 (d, J=2.4 Hz, 1H), 3.92 (s, 3H).

Step B: (3-methoxy-1-naphthyl) trifluoromethanesulfonate: To a solutionof 3-methoxynaphthalen-1-ol (2.10 g, 12.0 mmol, 1.00 eq) in DCM (40.0mL) was added DIEA (7.79 g, 60.3 mmol, 10.5 mL, 5.00 eq) andtrifluoromethanesulfonic anhydride (5.10 g, 18.1 mmol, 2.98 mL, 1.50 eq)at 0° C. The mixture was stirred at 25° C. for 1 hour. The mixture wasdiluted with DCM (30 mL) and water (10 mL) and extracted with DCM (20mL). The combined organic layers were washed with brine (5 mL), driedover Na₂SO₄ and concentrated under vacuum. The residue was purified bysilica gel chromatography (diethyl ether-ethyl acetate=20:1 to 10:1) togive (3-methoxy-1-naphthyl) trifluoromethanesulfonate (3.00 g, 8.52mmol, 70.7% yield, 87.0% purity) as a brown oil. ESI MS m/z 307.1[M+H]⁺.

Intermediate 31

7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine

Step A: 7-benzyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-2,4-diol: ToEtOH (600 mL) was added Na (5.56 g, 241 mmol, 5.73 mL, 2.40 eq) inportions. The reaction mixture was stirred for 1 hour. To the mixturewas added ethyl 1-benzyl-3-oxo-piperidine-4-carboxylate (30.0 g, 100mmol, 1.00 eq, HCl) and urea (14.5 g, 242 mmol, 13.0 mL, 2.40 eq). Thereaction mixture was stirred at 75° C. for 36 hours, and then thesolvent was removed under vacuum. The residue was dissolved in water (50mL) and acidified with HCl (120 mL, 2M). A white solid precipitated fromthe solution and was collected by filtration. The filter cake was driedunder vacuum to provide7-benzyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-2,4-diol (22.0 g, 83.8mmol, 83.2% yield, 98% purity) as a white solid. ¹HNMR (400 MHz,DMSO-d₆) δ=10.97 (br s, 1H), 10.66 (br s, 1H), 7.55-6.95 (m, 5H),3.81-3.50 (m, 2H), 3.26-2.91 (m, 2H), 2.77-2.58 (m, 2H), 2.34-2.09 (m,2H).

Step B: 7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine: Toa solution of DIEA (30.1 g, 233 mmol, 40.7 mL, 3.00 eq) in POCl₃ (330 g,2.15 mol, 200 mL) was added7-benzyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-2,4-diol (20.0 g, 77.7mmol, 1.00 eq). The reaction mixture was stirred at 110° C. for 5 hours.The reaction mixture was concentrated under vacuum. The residue wasdissolved in DCM (400 mL) and poured into saturated NaHCO₃ (200 mL). Themixture was extracted with DCM (2×400 mL). The combined organic layerswere washed with brine (100 mL), dried over Na₂SO₄ and concentratedunder vacuum. The residue was purified by silica gel chromatography(diethyl ether:DCM=10:1 to 0:1) to give7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (7.70 g,26.2 mmol, 33.7% yield) as a brown oil. ¹HNMR (300 MHz, chloroform-d)δ=7.43-7.28 (m, 5H), 3.73 (s, 2H), 3.66 (br s, 2H), 2.84 (br s, 4H)

Intermediate 32

tert-butyl4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-(methylsulfonyl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate

Step A:tert-butyl4-hydroxy-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate:To a stirred solution of 1-tert-butyl4-ethyl-3-oxopiperidine-1,4-dicarboxylate (44.0 g, 162 mmol, 1.00 eq) inMeOH (1.00 mL) at 25° C. under nitrogen was added a solution of NaOMe(35.0 g, 649 mmol, 4.00 eq) in MeOH (600 mL) by syringe followed by2-methylisothiourea (61.1 g, 324 mmol, 2.00 eq, H₂SO₄). After stirringat 25° C. for 16 hours, the reaction mixture was concentrated underreduced pressure to removed MeOH. The residue was suspended in 500 mL ofethyl acetate and 500 mL of water and stirred rapidly. The reactionmixture was adjusted to pH 5 with HCl (2 M). The precipitate wasfiltered and the white solid was washed with ethyl acetate and driedunder vacuum to givetert-butyl4-hydroxy-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(33.0 g, 103 mmol, 63.8% yield, 93.2% purity) as a white solid, whichwas used directly in the next step without further purification. ¹H NMR(400 MHz, DMSO-d6) δ=4.19 (s, 2H), 3.49 (br s, 2H), 2.46 (s, 3H), 2.35(br t, J=5.2 Hz, 2H), 1.42 (s, 9H).

Step B: give tert-butyl2-methylsulfanyl-4-(trifluoromethylsulfonyloxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate: To a stirred suspension of tert-butyl4-hydroxy-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(15.0 g, 50.4 mmol, 1.00 eq) in DCM (200 mL) was added DIEA (26.1 g, 202mmol, 35.2 mL, 4.00 eq) at 0° C. under nitrogen and followed bytrifluoromethanesulfonic anhydride (28.5 g, 101 mmol, 16.6 mL, 2.00 eq)by syringe. Immediately a brown solution formed. The reaction mixturewas stirred at 25° C. for 12 hours. The reaction mixture was purified bycolumn chromatography (SiO₂, Petroleum ether/Ethyl acetate=1:0 to 10:1)to give tert-butyl2-methylsulfanyl-4-(trifluoromethylsulfonyloxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (16.7 g, 35.7 mmol, 70.9% yield, 91.9%purity) as a white solid. ESI MS m/z 374.0 [M+H]⁺.

Step C: tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate:To a stirred solution of tert-butyl2-methylsulfanyl-4-(trifluoromethylsulfonyloxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (16.7g, 38.9 mmol, 1.00 eq) in DMF (100 mL) was added DIEA (10.0 g, 77.9mmol, 2.00 eq) and benzyl piperazine-1-carboxylate (9.41 g, 42.8 mmol,1.10 eq) The reaction was heated to 100° C. and stirred for 1 hour undera nitrogen atmosphere. The reaction mixture was diluted with water (150mL) and the reaction mixture was adjusted to pH 5 with HCl (2 M) andextracted with DCM (3×200 mL). The combined organic layers were washedwith saturated NaHCO₃ (3×150 mL), brine (3×150 mL) and H₂O (3×150 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(18.1 g, 36.2 mmol, 93.0% yield, 94.1% purity) as a yellow solid, whichwas used directly in the next step without further purification. ESI MSm/z 500.1 [M+H]⁺.

Step D: tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-methylsulfonyl-6×8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate:To a stirred solution oftert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(14.4 g, 28.9 mmol, 1.00 eq) in DCM (150 mL) at 0° C. under nitrogen wasadded meta-chloroperoxybenzoic acid (17.4 g, 101 mmol, 3.50 eq) as asolid. After stirring at 0° C. for 2 hours under a nitrogen atmosphere,the reaction mixture was diluted with water (300 mL) and the reactionmixture was adjusted to pH 8 with saturated aqueous NaHCO₃ and extractedwith DCM (3×200 mL). The combined organic layers were washed with brine(3×200 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to dryness. The residue was purified by column chromatography(SiO2, Petroleum ether/Ethyl acetate=10:1 to 1:2) to give tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-methylsulfonyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(11.0 g, 19.7 mmol, 68.6% yield, 95.4% purity) as a white solid. ESI MSm/z 532.1 [M+H]⁺.

Intermediate 33

tert-butyl (1-bromoisoquinolin-3-yl)carbamate

Step A: A mixture of 1-bromoisoquinolin-3-amine (400 mg, 1.79 mmol, 1.00eq) and tert-butoxycarbonyl tert-butyl carbonate (3.91 g, 17.9 mmol,4.12 mL, 10.0 eq) was stirred at 70° C. for 16 hours. The residue waspurified by column chromatography (SiO₂, diethyl ether/ethyl acetate5:1) to give tert-butyl N-(1-bromo-3-isoquinolyl) carbamate (400 mg,1.24 mmol, 69.2% yield) as a yellow solid. ESI MS m/z 322.1, 324.1[M+H]⁺.

Intermediate 34

3-methoxy-6-methylnaphthalen-1-yl trifluoromethanesulfonate

Step A: 3-methoxynaphthalen-1-ol: To a solution of naphthalene-1,3-diol(40.0 g, 250 mmol, 1.00 eq) in MeOH (800 mL) was added HCl (4 M, 750 mL,12.0 eq, 4 M in MeOH) at 0° C. The mixture was warmed up to 18° C. andstirred for 30 hours. The mixture was concentrated under vacuum. Theresidue was purified by column chromatography over silica gel (petroleumether/ethyl acetate 100/1 to 1/1). The desired fractions were collectedand concentrated under vacuum to give 3-methoxynaphthalen-1-ol (17.7 g,96.5 mmol, 38.6% yield, 95% purity) as a red oil. ¹H NMR (400 MHz,Chloroform-d) δ=8.17 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.50(ddd, J=1.2, 6.8, 8.0 Hz, 1H), 7.38 (ddd, J=1.2, 6.8, 8.0 Hz, 1H), 6.81(d, J=2.0 Hz, 1H), 6.76 (br s, 1H), 6.62 (d, J=2.4 Hz, 1H), 3.91 (s,3H).

Step B: tert-butyl-[(3-methoxy-1-naphthyl)oxy]-dimethyl-silane: To asolution of 3-methoxynaphthalen-1-ol (20.0 g, 115 mmol, 1.00 eq) andimidazole (23.5 g, 344 mmol, 3.00 eq) in THF (400 mL) was added TBSCl(26.0 g, 172 mmol, 21.1 mL, 1.50 eq) dropwise at 0° C. The mixture waswarmed up to 25° C. and stirred for 16 hours. The mixture was dilutedwith petroleum ether (600 mL) and ethyl acetate (200 mL), and thenwashed with water (1×200 mL) and brine (1×200 mL). The separated organiclayer was dried over sodium sulfate, filtered and concentrated undervacuum. The residue was purified by column chromatography over silicagel (petroleum ether/ethyl acetate 100/1 to 10/1).tert-butyl-[(3-methoxy-1-naphthyl)oxy]-dimethyl-silane (28.0 g, 97.1mmol, 84.6% yield) was obtained as a colorless oil. ¹H NMR (400 MHz,Chloroform-d) δ=8.01 (d, J=8.4 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.35(dt, J=1.2, 7.6 Hz, 1H), 7.24 (dt, J=1.2, 7.6 Hz, 1H), 6.71 (d, J=2.0Hz, 1H), 6.48 (d, J=2.4 Hz, 1H), 3.82 (s, 3H), 1.02 (s, 9H), 0.23 (s,6H).

Step C:tert-butyl-[[3-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]oxy]-dimethyl-silaneandtert-butyl((3-methoxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)oxy)dimethylsilane:A mixture of tert-butyl-[(3-methoxy-1-naphthyl) oxy]-dimethyl-silane(26.0 g, 90.1 mmol, 1.00 eq),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(45.8 g, 180 mmol, 2.00 eq), (1Z,5Z)-cycloocta-1,5-diene;2,4-dimethyl-BLAHbicyclo[1.1.0]butane (2.39 g, 3.61 mmol, 0.04 eq) and4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (1.45 g, 5.41 mmol, 0.06eq) in hexane (500 mL) was stirred at 100° C. under nitrogen atmospherefor 16 hours. The mixture was diluted with water (500 mL) and ethylacetate (1000 mL). The separated organic layer was washed with brine(1×500 mL), dried over sodium sulfate, filtered and concentrated undervacuum. The residue was purified by column chromatography over silicagel (petroleum ether/ethyl acetate 100/1 to 10/1). The desired fractionswere collected and concentrated under vacuum to give a mixture oftert-butyl-[[3-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]oxy]-dimethyl-silaneandtert-butyl((3-methoxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)oxy)dimethylsilane(38.0 g, 85.3 mmol, 94.61% yield, 93% purity) as a light yellow oil. ESIMS m/z 415.5 [M+H]⁺.

Step D: 8-[tert-butyl(dimethyl)silyl]oxy-6-methoxy-naphthalen-2-ol: To asolution of mixture (36.0 g, 86.9 mmol, 1.00 eq) oftert-butyl-[[3-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]oxy]-dimethyl-silaneandtert-butyl((3-methoxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)oxy)dimethylsilaneinin acetone (400 mL) was added a solution of Oxone (58.7 g, 95.6 mmol,1.10 eq) in H₂O (400 mL) at 0° C. The mixture was stirred at 0° C. for 1hour. The mixture was quenched with 5% aqueous sodium thiosulfatesolution (50 mL) and extracted with ethyl acetate (2×300 mL). Theextracts were combined and washed with water (1×200 mL), brine (1×200mL), dried over magnesium sulfate, filtered and the filtrate wasconcentrated under vacuum. The residue was purified by columnchromatography over silica gel (petroleum ether/ethyl acetate 200/1 to20/1). The desired fractions were collected and concentrated undervacuum to give8-[tert-butyl(dimethyl)silyl]oxy-6-methoxy-naphthalen-2-ol (9.00 g, 28.4mmol, 32.7% yield, 96% purity) as a colorless oil and5-[tert-butyl(dimethyl)silyl]oxy-7-methoxy-naphthalen-2-ol (9.00 g, 29.0mmol, 33.4% yield, 98% purity) as a white solid. ESI MS m/z 305.2 [M+H]⁺

Step E:[5-[tert-butyl(dimethyl)silyl]oxy-7-methoxy-2-naphthyl]trifluoromethanesulfonate:To a solution of5-[tert-butyl(dimethyl)silyl]oxy-7-methoxy-naphthalen-2-ol (11.0 g, 36.1mmol, 1.00 eq) and DIEA (14.0 g, 108 mmol, 18.9 mL, 3.00 eq) in DCM (150mL) was added Tf₂O (12.2 g, 43.4 mmol, 7.15 mL, 1.20 eq) dropwise at−40° C. The mixture was stirred for 1 hour. The mixture was diluted withdichloromethane (200 mL) and washed with water (1×200 mL) and brine(1×200 mL). The separated organic layer was dried over sodium sulfate,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography over silica gel (petroleum ether/ethyl acetate100/1 to 10/1). The desired fractions were collected and concentratedunder vacuum to give[5-[tert-butyl(dimethyl)silyl]oxy-7-methoxy-2-naphthyl]trifluoromethanesulfonate (13.0 g, 29.8 mmol, 82.4% yield, 100% purity)as a white solid. ESI MS m/z 436.9 [M+H]⁺

Step F: tert-butyl-[(3-methoxy-6-methyl-1-naphthyl)oxy]-dimethyl-silane:To a solution of[5-[tert-butyl(dimethyl)silyl]oxy-7-methoxy-2-naphthyl]trifluoromethanesulfonate(12.5 g, 28.6 mmol, 1.00 eq) and K₂CO₃ (11.9 g, 85.9 mmol, 3.00 eq) indioxane (160 mL) was added Pd(PPh₃)₄ (3.31 g, 2.86 mmol, 0.10 eq) andtrimethylboroxine (14.4 g, 57.3 mmol, 16.0 mL, 2.00 eq) under nitrogenatmosphere. The reaction was heated to 100° C. for 16 hours. The mixturewas diluted with ethyl acetate (200 mL) and then washed with water(1×200 mL) and brine (1×200 mL). The separated organic layer was driedover sodium sulfate, filtered and concentrated under vacuum. The residuewas purified by column chromatography over silica gel (petroleumether/ethyl acetate 100/1 to 5/1). The desired fractions were collectedand concentrated under vacuum to givetert-butyl-[(3-methoxy-6-methyl-1-naphthyl)oxy]-dimethyl-silane (8.00 g,24.6 mmol, 85.9% yield, 93% purity) as a colorless oil as red solid. ESIMS m/z 303.2 [M+H]⁺

Step G: 3-methoxy-6-methyl-naphthalen-1-ol: To a solution oftert-butyl-[(3-methoxy-6-methyl-1-naphthyl) oxy]-dimethyl-silane (8.00g, 26.5 mmol, 1.00 eq) in THF (100 mL) was added TBAF (10.4 g, 39.7mmol, 1.50 eq) at 0° C. The mixture was stirred at 0° C. for 3 hours.The mixture was diluted with water (100 mL) and ethyl acetate (200 mL).The separated organic layer was washed with brine (1×100 mL), dried oversodium sulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography over silica gel (petroleum ether/ethylacetate 50/1 to 5/1). The desired fractions were collected andconcentrated under vacuum to give 3-methoxy-6-methyl-naphthalen-1-ol(4.70 g, 25.0 mmol, 94.4% yield) as a red solid. ESI MS m/z 188.4 [M+H]⁺

Step H: 3-methoxy-6-methyl-1-naphthyl trifluoromethanesulfonate: To asolution of 3-methoxy-6-methyl-naphthalen-1-ol (4.70 g, 25.0 (mmol, 1.00eq) and DIEA (9.6 g, 74.9 mmol, 13.1 mL, 3.00 eq) in DCM (3.00 mL) wasadded Tf₂O (8.45 g, 30.0 mmol, 4.94 mL, 1.20 eq) dropwise at −40° C. Themixture was stirred for 1 hour. The mixture was diluted withdichloromethane (200 mL) and washed with water (1×200 mL) and brine(1×200 mL). The separated organic layer was dried over sodium sulfate,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography over silicagel (petroleum ether/ethyl acetate100/1 to 10/1) 3-methoxy-6-methyl-1-naphthyl trifluoromethanesulfonate(7.70 g, 24.0 mmol, 96.2% yield, 99.9% purity) was obtained as acolorless oil. ESI MS m/z 320.7 [M+H]⁺.

The following intermediates were prepared according to the preparationfor Intermediate 3, substituting the appropriate phenol for2-bromo-3-fluorophenol.

Intermediate No. Structure Name Intermediate 35

2-bromo-4-(methoxymethoxy)-1- (trifluoromethoxy)benzene Intermediate 36

2-bromo-4-(methoxymethoxy)-1- (trifluoromethyl)benzene Intermediate 37

2-bromo-1-(methoxymethoxy)-4- (trifluoromethoxy)benzene Intermediate 38

2-bromo-4-fluoro-3- (methoxymethoxy)-1-methylbenzene Intermediate 39

1-bromo-3-(methoxymethoxy)-5- (trifluoromethoxy)benzene Intermediate 40

2-bromo-1-methoxy-4- (methoxymethoxy)benzene Intermediate 41

2-bromo-1-(methoxymethoxy)-3- methylbenzene Intermediate 42

2-bromo-4-(methoxymethoxy)-1- methylbenzene Intermediate 43

1-bromo-4-(methoxymethoxy)-2- (trifluoromethoxy)benzene

Intermediate 44

2-bromo-3-fluoro-1-(methoxymethoxy)-4-methylbenzene

Step 1: 3-fluoro-4-methylphenol (1.016 g, 8.055 mmol) was placed in Cs₂(3.9 mL, 64.44 mmol) and was cooled to 0° C. Br₂ (0.4150 mL, 8.055 mmol)was added and the mixture was stirred at room temperature for 2 hrs. 10%Na₂S₂O₂ was added and the mixture was extracted with DCM. The organiclayers were combined, dried and filtered to provide2-bromo-3-fluoro-4-methylphenol (1.389 g, 6.775 mmol, 84.10% yield)which was used directly in the next step.

Step 2: 2-bromo-3-fluoro-1-(methoxymethoxy)-4-methylbenzene was preparedaccording to the procedure for Intermediate 8 using2-bromo-3-fluoro-4-methylphenol in place of 2-bromo-3-fluorophenol.

Intermediate 45

2-bromo-1-isopropoxy-4-(methoxymethoxy)benzene

Step 1: 4-isopropoxyphenol (1.00 g, 6.57 mmol) and TEA (1.83 mL, 13.1mmol) were placed in DCM (25 mL). Acetyl chloride (7.56 mL, 7.56 mmol)was added dropwise and the reaction was stirred at room temperature for2 hr. Water was added and the mixture was extracted with DCM. Theorganic layer was dried, filtered and concentrated to provide4-isopropoxyphenyl acetate (1.24 g, 6.38 mmol, 97.2% yield) which wasdirectly in the next step.

Step 2: 4-Isopropoxyphenyl acetate (1.24 g, 6.585 mmol) was placed inACN (20 mL) and N-bromosuccinimide (1.173 g, 6.590 mmol) was added. Themixture was stirred for 18 hr. Water was added and the mixture wasextracted with ether. The organic layers were combined, dried, andconcentrated to provide 3-bromo-4-isopropoxyphenyl acetate (1.584 g,5.800 mmol, 88.00% yield) which was directly in the next step.

Step 3: 3-Bromo-4-isopropoxyphenyl acetate (500 mg, 1.83 mmol) wasplaced in MeOH (7 mL). A solution of KOH (111 mg, 1.98 mmol) in water (2mL) was added to mixture and was stirred for 1 hr at room temperature.The reaction mixture was adjusted to pH 3 by the addition of 1N HCl. Themixture was extracted with DCM. The extracts were combined, dried,filtered and concentrated to provide crude 3-bromo-4-isopropoxyphenolwhich was used directly the next reaction.

Step 4: 2-Bromo-1-isopropoxy-4-(methoxymethoxy)benzene was preparedaccording to the procedure for Intermediate 8 using3-bromo-4-isopropoxyphenol in place of 2-bromo-3-fluorophenol

Intermediate 46

1-bromo-3-chloro-2-isopropyl-5-(methoxymethoxy)benzene

Step 1: 1-bromo-3-chloro-2-isopropyl-5-methoxybenzene (952 mg, 3.61mmol) was placed in DCM (3 mL) and was cooled to 0° C. BBr3 (9030 μL,9.03 mmol) was added and the reaction was stirred at 0° C. for 2 hr.Water was added and the mixture was extracted with DCM. The extractswere combined and concentrated. The resulting residue was purified bysilica gel (0-20% EtOAc in hexane) to provide3-bromo-5-chloro-4-isopropylphenol (575 mg, 2.30 mmol, 63.8% yield)

Step 2: 1-bromo-3-chloro-2-isopropyl-5-(methoxymethoxy)benzene wasprepared according to the procedure for Intermediate 8 using3-bromo-5-chloro-4-isopropylphenol in place of 2-

Intermediate 47

1-iodo-3-(methoxymethoxy)naphthalene

To a solution of 4-iodonaphthalen-2-ol (0.80 g, 3.0 mmol) in DCM (20 mL)was added N-ethyl-N-isopropylpropan-2-amine (1.1 mL, 5.9 mmol) andchloro(methoxy)methane (0.29 g, 3.6 mmol) and the reaction stirred atroom temperature for 4 hours, with additional chloro(methoxy)methane(0.15 g) being added after 2 hours. The reaction was washed with brineand concentrated in vacno. The material was purified by chromatographyusing a gradient of 0 to 10% EtOAc/hexanes as the eluent to give1-iodo-3-(methoxymethoxy)naphthalene (0.80 g, 25 mmol, 86% yield).

Intermediate 48

Step A: 2,4-dibromonaphthalen-1-amine: To a solution of Br₂ (246 g, 1.54mol, 79.3 mL) in AcOH (750 mL) was added a solution ofnaphthalen-1-amine (101 g, 705 mmol, 99.0 mL) in AcOH (500 mL) at roomtemperature and the reaction stirred at 70° C. for 1 hour. The reactionmixture was cooled to room temperature and filtered. The filter cake waswashed with AcOH (300 mL). The solid was next suspended in 20% aqueousof NaOH (1.2 L). The mixture was stirred for 20 minutes and filtered.The solid was washed with water (1 L) and dried under vacuum to give2,4-dibromonaphthalen-1-amine (200 g, 664 mmol, 94.2% yield) as graysolid. ES+APCI MS m/z 301.9 [M+H]⁺.

Step B: 4-bromo-1-diazonio-naphthalen-2-olate: To a solution of2,4-dibromonaphthalen-1-amine (60.0 g, 199 mmol) in AcOH (900 mL) andpropionic acid (150 mL) was added NaNO₂ (16.5 g, 239 mmol, 13.0 mL)portionwise at 5-8° C. over 30 minutes and the reaction mixture stirredat 5-8° C. for 30 minutes. The reaction mixture was poured intoice-water (4000 mL), the slurry filtered and the solid washed with water(2×50 mL) to give 4-bromo-1-diazonio-naphthalen-2-olate (150 g, wetcrude) which was used crude in the next step immediately. ¹H NMR (400MHz, CDCl₃) δ 8.12-8.10 (d, J=8.4 Hz, 1H), 7.62-7.58 (t, J=7.6 Hz, 1H),7.41-7.37 (t, J=7.6 Hz, 1H), 7.31-7.29 (d, J=8.0 Hz, 1H), 7.20 (s, 1H).

Step C: 4-bromonaphthalen-2-ol: To a solution of4-bromo-1-diazonio-naphthalen-2-olate (100 g, 402 mmol) in EtOH (2.00 L)was added portion-wise NaBH₄ (30.4 g, 803 mmol) at 13-15° C. over 1 hourand the reaction stirred at 15-18° C. for 3 hours. The reaction wasfiltered and concentrated to dryness. The residue was dissolved in DCM(1000 mL) and washed with water (500 mL×2). The organics were dried overNa₂SO₄ and concentrated to dryness. The residue was purified bychromatography eluting with petroleum ether/EtOAc (60/1→10/1) andmaterial re-purified by reversed phase HPLC to give4-bromonaphthalen-2-ol (40.0 g, 139 mmol, 17.3% yield, 77.4% purity) asa gray solid. ¹H NMR (400 MHz, CDCl₃) δ 8.07-8.05 (d, J=8.0 Hz, 1H),7.60-7.58 (d, J=7.6 Hz, 1H), 7.41-7.36 (m, 3H), 7.07 (s, 1H).

Step D: 3-benzyloxy-1-bromo-naphthalene: A mixture of4-bromonaphthalen-2-ol (30.0 g, 134 mmol), BnBr (25.3 g, 148 mmol, 17.6mL) and K₂CO₃ (55.7 g, 403 mmol) in MeCN (500 mL) was heated at 80° C.for 1 hr. The reaction mixture was filtered and concentrated to dryness.The residue was purified by silica gel column eluting with PE/EA (100/1to 60/1) to give 3-benzyloxy-1-bromo-naphthalene (40.0 g, 128 mmol, 95%yield). ¹H NMR (400 MHz, CDCl₃) δ 8.19-8.17 (d, J=8.0 Hz, 1H), 7.75-7.32(d, J=8.8 Hz, 1H), 7.64-7.63 (d, J=2.4 Hz, 1H), 7.52-7.37 (m, 7H),7.23-7.21 (d, J=2.0 Hz, 1H), 5.2 (s, 2H).

Intermediate 49 benzyl4-(7-(3-(benzyloxy)naphthalen-1-yl)-2-(methylsulfinyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

Step A: tert-butyl4-hydroxy-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate:To a solution of 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate(50.0 g, 184 mmol) in MeOH (1.00 L) under nitrogen was added NaOMe (49.8g, 921 mmol) and 2-methylisothiourea (62.4 g, 331 mmol, H₂SO₄). Thereaction mixture was stirred at 25° C. for 16 hours. HCl (2 M) was addedto the reaction mixture until pH˜5 and then the mixture was concentratedunder reduced pressure. The residue was suspended in 300 mL of ethylacetate and 300 mL of water. The suspension was filtered. The organicphase was washed with water (1×300 mL), brine (1×200 mL), dried overNaSO₄, filtered and concentrated to give tert-butyl4-hydroxy-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(51.0 g, 138 mmol, 75.4% yield, 81.0% purity) which was used directly inthe next reaction. ES+APCI MS m/z 298.2 [M+H]⁺.

Step B: tert-butyl2-methylsulfanyl-4-(trifluoromethylsulfonyloxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate:To a solution of tert-butyl4-hydroxy-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(51.0 g, 171 mmol) in DCM (500 mL) was added DIEA (44.3 g, 343 mmol,59.9 mL) and Tf₂O (72.6 g, 257 mmol, 42.4 mL) sequentially at 0° C.under nitrogen. The reaction mixture was warmed up to 25° C. and stirredfor 16 hours. The reaction mixture was concentrated and the residuepurified by column chromatography eluting with EtOAc/Petroleum 0→10%, togive tert-butyl2-methylsulfanyl-4-(trifluoromethylsulfonyloxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(46.0 g, 107 mmol, 62.4% yield) ES+APCI MS m/z 430.2 [M+H]⁺.

Step C: tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate:To a solution of tert-butyl2-methylsulfanyl-4-(trifluoromethylsulfonyloxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(46.0 g, 107 mmol in DMF (500 mL) was added DIEA (27.7 g, 214 mmol, 37.4mL) and benzyl piperazine-1-carboxylate (25.9 g, 117 mmol, 22.7 mL). Thereaction was heated to 100° C. for one hour under N₂ atmosphere. Thereaction mixture was poured into ethyl acetate (300 mL). The mixture waswashed with H₂O (300 mL×3). The organic phase was washed with brine (200mL), dried over anhydrous Na₂SO₄, concentrated in vacuo. The residue waspurified by column chromatography using 0→20% EtOAc/Petroleum as eluentto give tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(51.0 g, 96.9 mmol, 90.5% yield, 92.0% purity) ES+APCI MS m/z 500.3[M+H]⁺.

Step D: Benzyl4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:To a solution of tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(25.0 g, 50 mmol) in DCM (50 mL) was added TFA (85.6 g, 750 mmol, 55.6mL). The mixture was stirred at 25° C. for 1 hour. The reaction mixturewas concentrated under reduced pressure and the residue was dissolved in300 ml of ethyl acetate and 300 mL of water and Na₂CO₃ added until pH˜8.The organic layer was washed with water (1×300 mL), brine (1×200 mL) anddried over Na₂SO₄, filtered and concentrated under reduced pressure togive benzyl4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate.The product was used directly to the next step without furtherpurification. ES+APCI MS m/z 400.2 [M+H]⁺.

Step E: benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate: A mixture of3-benzyloxy-1-bromo-naphthalene (16.3 g, 52.1 mmol), benzyl4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(16.0 g, 40.1 mmol), Cs₂CO₃ (32.6 g, 100 mmol), Pd₂(dba)₃ (5.50 g, 6.01mmol) and RuPhos (3.74 g, 8.01 mmol) in dioxane (300 mL) was degassedwith N₂ 3 times and the mixture stirred at 85° C. for 5 hour under N₂atmosphere. The reaction mixture was quenched by addition water (200 mL)at 0° C., and extracted with EtOAc (3×200 mL). The combined organiclayers were washed with brine (3×150 mL), dried over Na₂SO₄, filteredand concentrated under reduced pressure. The residue was purified bycolumn chromatography eluting with 10→20% MeOH/DCM to give benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate (16.0 g, 22.8 mmol, 56.9% yield,90.0% purity ES+APCI MS m/z 632.5 [M+H]⁺.

Step F: benzyl4-[7(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(8.00 g, 12.7 mmol) in DCM (200 mL) was added m-CPBA (2.73 g, 12.7 mmol,80.0% purity) at 0° C. under nitrogen atmosphere. The reaction mixturewas stirred for two hours under 0° C. The reaction mixture was quenchedby addition Na₂S₂O₃ (10 mL) at 0° C., and then diluted with water (100mL) and extracted with DCM (200 mL). The combined organic layers werewashed with brine (200 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by columnchromatography eluting with 0→10% MeoH/DCM to benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(3.50 g, 4.92 mmol, 38.8% yield, 91.0% purity) ES+APCI MS m/z 648.5[M+H]⁺.

Intermediate 50 tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-methylsulfonyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate

Step A: tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-methylsulfonyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate:To a stirred solution oftert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(14.4 g, 28.9 mmol) in DCM (150 mL) was added m-CPBA solid (17.4 g, 101mmol) at 0° C. under nitrogen. After stirring at 0° C. for 2 hours, thereaction mixture was diluted with water (300 mL) and basified withsaturated NaHCO₃ aqueous solution to pH˜8 and then extracted with DCM(3×200 mL). The combined organic layers were washed with brine (3×200mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate 10/1 to 1/2) to give tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-methylsulfonyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(11.0 g, 19.7 mmol, 68.6% yield, 95.4% purity). ES+APCI MS m/z 532.1[M+H]⁺.

Intermediate 51 4-bromo-5-methyl-1-tetrahydropyran-2-yl-indazole

Step A: 4-bromo-5-methyl-1-tetrahydropyran-2-yl-indazole: To a mixtureof 4-bromo-5-methyl-1H-indazole (3 g, 14.2 mmol) and3,4-dihydro-2H-pyran (2.39 g, 28.4 mmol, 2.60 mL) in DCM (30 mL) wasadded TsOH*H₂O (270 mg, 1.42 mmol) and the mixture stirred at 15° C. for2 hours. After completion, the reaction mixture was concentrated undervacuum and the residue purified by column chromatography using 5→20&EtOAc/Petroleum Ether as eluent to give4-bromo-5-methyl-1-tetrahydropyran-2-yl-indazole (4 g, 13.6 mmol, 95.3%yield) as white solid. ¹H NMR (400 MHz, chloroform-d) δ 8.01 (s, 1H),7.47 (d, J=8.4 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 5.70 (dd, J=2.8, 9.2 Hz,1H), 4.05-3.96 (m, 1H), 3.79-3.70 (m, 1H), 2.66-2.44 (m, 4H), 2.25-2.04(m, 2H), 1.84-1.56 (m, 3H).

Intermediate 524-bromo-5-methoxy-1-(tetrabydro-2H-pyran-2-yl)-1H-indazole

4-bromo-5-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole was preparedfollowing Intermediate 51 substituting 4-bromo-5-methoxy-1H-indazole for4-bromo-5-methyl-1H-indazole in Step A. ¹H NMR (400 MHz, chloroform-d) δ8.00 (s, 1H), 7.53 (d, J=9.2 Hz, 1H), 7.16 (d, J=9.2 Hz, 1H), 5.70 (dd,J=2.8, 9.2 Hz, 1H), 4.04-3.98 (m, 1H), 3.96 (s, 3H), 2.55-2.49 (m, 1H),2.23-2.05 (m, 2H), 1.83-1.69 (m, 3H).

Intermediate 53 3-(benzyloxy)-1-bromo-2-methylnaphthalene

Step A: ethyl 2-methyl-3-oxo-4-phenyl-butanoate. To a dried 250 mlthree-necked flask was added ethyl 3-oxo-4-phenyl-butanoate (4.00 g,19.4 mmol.), THF (50.0 mL), sodium hydride (931 mg, 23.3 mmol) and thereaction stirred for 0.5 hours at 0° C. A solution of methyl iodide(3.03 g, 21.3) was next added drop-wise. After addition was completed,the reaction mixture was warmed to 20° C. and stirred for two hours at20° C. The reaction mixture was quenched by addition of water (10.0 mL)at 20° C. and then diluted with ethyl acetate (20.0 mL) and the layersseparated. The aqueous layer was next extracted with ethyl acetate (20.0mL×3). The combined organic layers were washed with brine (30.0 mL),dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to give a residue. The residue was purified by columnchromatography (SiO2, Petroleum ether:Ethyl acetate 20:1 to 10:1) togive ethyl 2-methyl-3-oxo-4-phenyl-butanoate (3.60 g, 16.3 mmol, 84.3%yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ=7.38-7.28 (m, 3H),7.25-7.19 (m, 2H), 4.22-4.15 (m, 2H), 3.87 (d, J=2.0 Hz, 2H), 3.65 (q,J=7.2 Hz, 1H), 1.34 (d, J=7.2 Hz, 3H), 1.30-1.26 (m, 3H).

Step B: 2-methylnaphthalene-1,3-diol. A solution of ethyl2-methyl-3-oxo-4-phenyl-butanoate (3.60 g, 16.3 mmol) in concentratedsulfuric acid (19.9 g, 203 mmol) was stirred at 15° C. for 12 hours. Thereaction mixture was poured into ice-water (30.0 mL) and the resultingsolid collected by filtration and dried under vacuum to afford2-methylnaphthalene-1,3-diol (1.80 g, 10.3 mmol, 63.2% yield) as a redsolid. ¹H NMR (400 MHz, CDCl₃) δ=8.02 (d, J=8.0 Hz, 1H), 7.65-7.54 (m,1H), 7.41 (t, J=7.2 Hz, 1H), 7.36-7.31 (m, 1H), 6.80 (s, 1H), 4.29-4.20(s, 2H), 2.41-2.24 (s, 3H).

Step C: 3-methoxy-2-methyl-naphthalen-1-ol. 2-methylnaphthalene-1,3-diol(1.70 g, 9.76 mmol) was added to HCl/MeOH (2 M, 35.0 mL) and the resultmixture was stirred at 30° C. for 3 days. The reaction was concentratedin vacuo and the residue purified by Prep-TLC (Petroleum ether:Ethylacetate 1:1) to give 3-methoxy-2-methyl-naphthalen-1-ol (800 mg, 4.25mmol, 43.5% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ=8.02 (d,J=8.4 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.44-7.38 (m, 1H), 7.37-7.31 (m,1H), 6.79 (s, 1H), 5.14 (s, 1H), 3.94 (s, 3H), 2.29 (s, 3H).

Step D: (3-methoxy-2-methyl-1-naphthyl)trifluoromethanesulfonate. To amixture of 3-methoxy-2-methyl-naphthalen-1-ol (800 mg, 4.25 mmol.) andpyridine (504 mg, 6.38 mmol) in DCM (10.0 mL) was added trifluoroaceticanhydride (1.44 g, 5.10 mmol) dropwise at 0° C. under N₂ atmosphere. Themixture was warmed to 20° C. and stirred for an additional 5 hours. Thesolvent was removed under vacuum and the residue purified by Prep-TLC(Petroleum ether:Ethyl acetate 1.1) to give(3-methoxy-2-methyl-1-naphthyl)trifluoromethanesulfonate (1.30 g, 4.06mmol, 95.5% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ=7.97 (d,J=7.6 Hz, 1H), 7.79-7.74 (m, 1H), 7.52-7.43 (m, 2H), 7.14 (s, 1H), 3.99(s, 3H), 2.42 (s, 3H).

Step E: 1-bromo-3-methoxy-2-methyl-naphthalene: In a sealed tube wasadded (3-methoxy-2-methyl-1-naphthyl)trifluoromethanesulfonate (466 mg,1.45 mmol), t-Bu-Brettphos (154 mg, 290 umol), potassium bromide (259mg, 2.17 mmol), PEG-200 (175 mg), 2-butanone (157 mg, 2.17 mmol) andPd₂(dba)₃ (133 mg, 145 umol) in toluene (10.0 mL) and the mixturede-gassed with N2 for 5 minutes. Next, triisobutylaluminum (431 mg, 2.17mmol) was added drop-wise at 20° C. The mixture was heated to 100° C.for 24 hrs. The reaction mixture was poured into water (30.0 mL) and theaqueous layer extracted with ethyl acetate (20.0 mL×3). The combinedorganics were washed with brine (30.0 mL), dried over anhydrous sodiumsulfate and concentrated in vacuo to give a residue which waspre-purified by column chromatography (Petroleum ether:Ethyl acetate10:1) and then by Prep-TLC (Petroleum ether:Ethyl acetate 10:1) to give1-bromo-3-methoxy-2-methyl-naphthalene (700 mg, 2.79 mmol, 64.1% yield)as a white solid. ¹H NMR (400 MHz, CDCl₃) δ=8.26-8.17 (m, 1H), 7.73-7.69(m, 1H), 7.47-7.40 (m, 2H), 7.09 (s, 1H), 3.98-3.95 (m, 3H), 2.56 (s,3H).

Step F: 4-bromo-3-methyl-naphthalen-2-ol: To a solution of1-bromo-3-methoxy-2-methyl-naphthalene (580 mg, 2.31 mmol) andtetrabutylammonium iodide (2.13 g, 5.78 mmol) in DCM (11.0 mL) cooled to−78° C. was added a solution of BCl₃ (1 M, 5.78 mL) dropwise over aperiod of 10 minutes while under N₂. The reaction mixture was warmed to0° C. and stirred for 2 hours at room temperature. Next the solvent wasremoved under vacuum and the residue was purified by Prep-TLC (Petroleumether:Ethyl acetate 5:1) to give 4-bromo-3-methyl-naphthalen-2-ol (500mg, 2.11 mmol, 91.3% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃)δ=8.26-8.15 (m, 1H), 7.63 (dd, J=3.6, 6.0 Hz, 1H), 7.45-7.38 (m, 2H),7.11 (s, 1H), 5.09 (s, 1H), 2.60 (s, 3H), 1.56 (s, 3H).

Step G: 3-benzyloxy-1-bromo-2-methyl-naphthalene. To a mixture of4-bromo-3-methyl-naphthalen-2-ol (265 mg, 1.12 mmol) and benzyl bromide(201 mg, 1.18 mmol) in acetonitrile (3.00 mL) was added potassiumcarbonate (310 mg, 2.24 mmol) in one portion at 20° C. under N₂. Themixture was next stirred at 60° C. for two hours. The solvent wasremoved under vacuum and the residue purified by Prep-TLC (Petroleumether:Ethyl acetate 5:1) to give the3-benzyloxy-1-bromo-2-methyl-naphthalene (250 mg, 695 umol, 31.0% yield,91.0% purity) as a white solid. ES+APCI MS m/z 327.0, 329.0 [M+H]⁺.

Intermediate 54tert-butyl-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

Step A: (4-bromo-2-naphthyl) 2,2-dimethylpropanoate. To a solution of4-bromonaphthalen-2-ol (10 g, 44.8 mmol) and TEA (9.07 g, 89.7 mmol) inDCM (200 mL) was added 2,2-dimethylpropanoyl chloride (8.11 g, 67.2mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 min. Treaction mixture was quenched by addition of water (50 mL) and thelayers separated. The organic layer was washed with brine (30 mL), driedover Na₂SO₄ filtered and concentrated under vacuum. The residue waspurified by silica gel chromatography (PE:EA=1:0 to 100:1) to give(4-bromo-2-naphthyl) 2,2-dimethylpropanoate (9 g, 29.3 mmol, 65.4%yield) as a red oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ=8.22 (d, J=8.0 Hz,1H), 7.83-7.77 (m, 1H), 7.63-7.49 (m, 4H), 1.41 (s, 9H).

Intermediate 55 tert-butyl4-(2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

Step A: 7-benzyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-2,4-diol. ToEtOH (600 mL) was added Na (5.56 g, 241 mmol) in portions and themixture stirred for 1 hour. To this solution was added ethyl1-benzyl-3-oxo-piperidine-4-carboxylate (30.0 g, 100 mmol) and urea(14.5 g, 242 mmol) and the reaction mixture stirred at 75° C. for 36hours. The solvent was removed under vacuum and the residue dissolved inwater (50 mL) and acidified by addition of HCl (120 mL, 2M) at whichpoint a solid precipitated. The solid was filtered and the filter cakedried under vacuum to give7-benzyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-2,4-diol (22.0 g, 83.8mmol). ¹HNMR (400 MHz, DMSO-d₆) δ=10.97 (br s, 1H), 10.66 (br s, 1H),7.55-6.95 (m, 5H), 3.81-3.50 (m, 2H), 3.26-2.91 (m, 2H), 2.77-2.58 (m,2H), 2.34-2.09 (m, 2H).

Step B: 7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine. Toa solution of DIEA (30.1 g, 233 mmol) in POCl₃ (330 g, 2.15 mol) wasadded 7-benzyl-6,8-dihydro-5H-pyrido[3,4-d] pyrimidine-2,4-diol (20.0 g,77.7 mmol) and the reaction mixture stirred at 110° C. for 5 hours. Uponcompletion, the reaction mixture was concentrated under vacuum. Theresidue was dissolved in DCM (400 mL) and poured into sat. NaHCO₃ (200mL) and the layers separated. The aqueous layer was extracted with DCM(2×400 mL). The combined organics were washed with brine (100 mL), driedover Na₂SO₄ and concentrated under vacuum. The residue was purified bysilica gel chromatography (PE/DCM=10/1 to 0/1) to give7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (7.70 g,26.2 mmol). ¹HNMR (300 MHz, chloroform-d) δ=7.43-7.28 (m, 5H), 3.73 (s,2H), 3.66 (br s, 2H), 2.84 (br s, 4H).

Step C: tert-butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate. To a solution of7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (17.3 g,58.8 mmol) in DMSO (200 mL) was added DIEA (19.0 g, 147 mmol) andtert-butyl piperazine-1-carboxylate (11.5 g, 61.7 mmol) and the mixturestirred at 55° C. for 10 hours. The reaction mixture was poured intoethyl acetate (200 mL) and washed with water (3×200 mL). The combinedorganics were washed with brine (200 mL), dried over anhydrous Na₂SO₄and concentrated under vacuum to give a residue. The residue waspurified by trituration from MTBE (200 mL) to give tert-butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (24 g, 52.9 mmol). ES+APCI MS m/z 444.2 [M+H]⁺.

Step D: tert-Butyl4-[7-benzyl-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:A mixture of 3-morpholinopropan-1-ol (11.8 g, 81.1 mmol), tert-butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(18 g, 40.5 mmol), BINAP (5.05 g, 8.11 mmol), t-BuONa (9.74 g, 101 mmol)and Pd₂(dba)₃ (3.71 g, 4.05 mmol) in toluene (300 mL) was degassed andpurged with N₂ 3 times, and the mixture stirred at 110° C. for 3 hoursunder N₂ atmosphere. The reaction mixture was poured into H₂O (200 mL)and the aqueous layer extracted with ethyl acetate (3×300 mL). Thecombined organics were washed with brine (200 mL), dried over anhydrousNa₂SO₄ and concentrated under vacuum to give a residue. The residue waspurified by column chromatography (SiO2, Petroleum ether/Ethylacetate=100/1 to 5/1) to give tert-Butyl4-[7-benzyl-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(14 g, 22.5 mmol). ES+APCI MS m/z 553.4 [M+H]⁺.

Step E: tert-butyl4-[2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate. To a solution of tert-butyl4-[7-benzyl-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(14 g, 25.3 mmol) in MeOH (1 L) was added dry Pd/C (3 g, 10% purity)under N₂. The suspension was degassed under vacuum and purged with H₂several times. The mixture was stirred under H₂ (15 psi) at 40° C. for10 hours. The mixture was filtered and the filtrate concentrated invacuo to give a residue. The residue was purified by reversed phaseflash [water (0.1 TFA)/acetonitrile] to give tert-butyl4-[2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate (6.5 g, 13.9 mmol). ES+APCI MS m/z 463.4[M+H]⁺.

Intermediate 56

Naphthalen-1-yl trifluoromethanesulfonate. alpha-Naphthol (4 g, 27.74mmol) was dissolved in DCM (200 mL) in a 3 neck flask. The reaction wascooled to 10° C. in a water bath. N-ethyl-N-isopropylpropan-2-amine(4.846 ml, 27.74 mmol) and trifluoromethanesulfonic anhydride (4.668 ml,27.74 mmol) were added to the solution dropwise. The reaction wasstirred at 10° C. for 2 hours. TLC (25% EtOAc, UV vis) showed reactioncomplete. The organics were with water (2×) and brine (2×). The organicswere dried over MgSO4 and concentrated in vacuo. The concentrate waspurified using normal phase chromatography on the CombiFlash (0%-12%EtOAc:Hexanes). All fractions containing clean product were combined andconcentrated in vacuo to give naphthalen-1-yl trifluoromethanesulfonate(6.77 g, 24.51 mmol, 88.34% yield).

Intermediate 57

Tert-butyl (S)-2-(hydroxymethyl)-4-methylpiperazine-1-carboxylate

To a solution of (S)-1-Boc-2-hydroxymethylpiperazine (1.0 g, 4.62 mmol)in DCE (92.47 ml, 4.624 mmol) was added formaldehyde (3.474 ml, 46.24mmol) (37% in water) followed by sodium triacetoxyborohydride (4.9 g,23.12 mmol). The mixture was stirred vigorously at room temperature for2.5 hours. The mixture was treated with saturated sodium bicarbonate (30mL), stirred for 10 min then extracted with DCM (3×10 mL). The combinedorganic phases were dried over sodium sulfate, filtered andconcentrated. ES+APCI MS m/z 231.1 [M+H]⁺.

Intermediate 58

Tert-butyl (R)-2-(hydroxymethyl)-4-methylpiperazine-1-carboxylate

Title compound was prepared as in Intermediate 57, substitutingtert-butyl (R)-2-(hydroxymethyl)piperazine-1-carboxylate for(S)-1-Boc-2-hydroxymethylpiperazine. ES+APCI MS m/z 231.1 [M+H]⁺

Intermediate 59

1-bromo-3-chloro-2-fluoro-5-(methoxymethoxy)benzene

To a round bottom flask was added THF (8.87 ml, 4.44 mmol) followed bysodium hydride, 60% dispersion in mineral oil (0.213 g, 5.32 mmol). Themixture was cooled to 0° C. then 3-bromo-5-chloro-4-fluorophenol (1.0 g,4.44 mmol) was added portionwise. Once the bubbling had ceased theresulting dark mixture was stirred at 0° C. for 30 min. Thenchloromethyl methyl ether (0.421 ml, 5.54 mmol) was added and themixture was warmed to ambient temperature where it was stirred for 2 hr.A saturated aqueous ammonium chloride solution was added and the mixturewas extracted with DCM. The organic layer was dried over sodium sulfate,filtered and concentrated. Crude material was chromatographed (0-15%EtOAc in hexanes) to provide product as clear oil.

Intermediate 604-bromo-1-tetrahydropyran-2-yl-5-(trifluoromethyl)indazole

Step A: 4-bromo-1-tetrahydropyran-2-yl-5-(trifluoromethyl)indazole: To asolution of 4-bromo-5-(trifluoromethyl)-1H-indazole (500 mg, 1.89 mmol,1 eq) in DCM (10 mL) was added 3,4-dihydro-2H-pyran (476 mg, 5.66 mmol,517 uL, 3 eq) and TsOH·H₂O (35.9 mg, 188 umol, 0.1 eq). The mixture wasstirred at 15° C. for 1 hour. The mixture was concentrated. The residuewas purified by column chromatography (SiO₂, PE:EA=10:1 to 1:1) to give4-bromo-1-tetrahydropyran-2-yl-5-(trifluoromethyl)indazole (480 mg, 1.37mmol, 72.9% yield) as yellow oil. ¹H NMR (400 MHz, chloroform-d) δ 8.20(s, 1H), 7.69-7.63 (m, 2H), 5.70 (dd, J=2.8, 8.8 Hz, 1H), 4.05-3.96 (m,1H), 3.79-3.70 (m, 1H), 2.56-2.50 (m, 1H), 2.27-2.04 (m, 2H), 1.80-1.74(m, 2H), 1.60-1.54 (m, 1H).

Intermediate 61

8-bromo-6-(methoxymethoxy)quinoline: A stirred suspension of8-bromoquinolin-6-ol (1.00 g, 4.46 mmol) in DCM (20 mL) was cooled to 0°C. and diisopropylethylamine (1.2 mL, 6.7 mmol, 1.5 eq.) was addedfollowed by chloro(methoxy)methane (0.41 mL, 5.4 mmol, 1.2 eq.) dropwiseand the reaction mixture was warmed to room temperature overnight.Concentrated aqueous ammonia (0.5 mL, ˜5 mmol) was next added and theresulted mixture was stirred for 1 hour at room temperature. The mixturewas evaporated in vacuo and chromatographed on silica gel, Redisep 40 g,using 20% EtOAc/hexane as eluent to give a colorless powder (0.52 g,44%). ES+APCI MS m/z 268.0, [M+H]⁺.

Intermediate 62

To a solution of but-3-enenitrile (80.0 g, 1.19 mol, 96.4 mL, 1.00 eq)in tert-butanol (130 mL) and petroleum ether (480 mL) was added asolution of Br₂ (191 g, 1.19 mol, 61.5 mL, 1.00 eq) in tert-butanol (130mL). The mixture was stirred at 10° C. for 4 hours. The mixture was usedinto next step without any workup.

To the above mixture (274 mL) was added a solution ofN,N′-dibenzylethane-1,2-diamine (160 g, 445 mmol, 157 mL, 2 HOAc) andEt₃N (178 g, 1.76 mol, 245 mL) in toluene (300 mL). After was stirred at110° C. for 2 hours, the mixture was filtered and the filtrate wasconcentrated under vacuum. The residue was purified by columnchromatography (SiO₂, petroleum ether/ethyl acetate=3/1) to give2-(1,4-dibenzylpiperazin-2-yl)acetonitrile (75.0 g, 246 mmol, two steps55.7% yield) as a yellow solid. LCMS [ESI, M+1]: 306.

¹H NMR (400 MHz, chloroform-d) δ=7.37-7.23 (m, 10H), 3.80 (d, J=13.2 Hz,1H), 3.60-3.42 (m, 3H), 3.06-2.96 (m, 1H), 2.95-2.83 (m, 1H), 2.69-2.53(m, 4H), 2.52-2.35 (m, 3H).

To a solution of 2-(1,4-dibenzylpiperazin-2-yl)acetonitrile (160 g, 524mmol, 1.00 eq) in dichloroethane (1.50 L) was added 1-chloroethylcarbonochloridate (300 g, 2.10 mol, 4.00 eq) at 15° C. After stirred at85° C. for 48 h, the mixture was concentrated under vacuum. The residuewas then taken up into methanol (1.50 L) and heated to reflux for 1hour. The mixture was concentrated. The solid was treated with methyltert-butyl ether (1.00 L), 2-piperazin-2-ylacetonitrile (Intermediate62, 90.0 g, 454 mmol, 86.7% yield, 2HCl) was obtained as a white solidand used for next step without further purification.

¹H NMR (400 MHz, DMSO-d6) δ=10.19 (br s, 2H), 4.01-3.73 (m, 1H),3.69-3.41 (m, 4H), 3.32 (dt, J=2.8, 13.2 Hz, 1H), 3.27-3.10 (m, 3H).

Intermediate 63

To a solution of tert-butyl(3R)-3-(hydroxymethyl)piperazine-1-carboxylate (80.0 g, 370 mmol, 1.0eq) in Ethyl acetate (1400 mL) was added NaHCO₃ (93.2 g, 1.11 mol, 43.2mL, 3.0 eq), H₂O (700 mL) and benzyl carbonochloridate (82.0 g, 481mmol, 68.4 mL, 1.30 eq). The mixture was stirred at 25° C. for 12 hour.After completion, the organic phase was separated, washed with water(500 mL×2) dried over Na₂SO₄ and filtered. The solvent was removed undervacuum to give a residue. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=40/1 to 1/1). Theproduct 1-benzyl 4-tert-butyl(2R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate (85.0 g, 235 mmol,64% yield, 96% purity) was obtained as a yellow oil. LCMS [ESI, M-99]:251.

To a solution of 1-benzyl 4-tert-butyl(2R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate (20.0 g, 57.1 mmol,1.0 eq) in 2-Methyltetrahydrofuran (240 mL) was added TEA (17.3 g,171.23 mmol, 23.8 mL, 3.0 eq) and methanesulfonyl chloride (7.74 g, 67.6mmol, 5.23 mL, 1.18 eq). The mixture was stirred at 20° C. for 1 hour.The reaction mixture was quenched by addition H₂O 150 mL at 20° C. Thereaction mixture was extracted with Ethyl acetate (300 mL×2). Theorganic layers were washed with H₂O (100 mL), dried over Na₂SO₄, andfiltered. The solvent was removed under vacuum. 1-benzyl 4-tert-butyl(2R)-2-(methylsulfonyloxymethyl)piperazine-1,4-dicarboxylate (22.0 g,crude) was obtained as a yellow oil. The crude product was used directlyto the next step without further purification.

To a solution of 1-benzyl 4-tert-butyl(2R)-2-(methylsulfonyloxymethyl)piperazine-1,4-dicarboxylate (22.0 g,51.3 mmol) in DMA (150 mL) was added NaCN (10.4 g, 211 mmol). Themixture was stirred at 60° C. for 12 hour. The solvent was removed undervacuum to give a oil residue. The residue was diluted with H₂O (40.0 mL)and extracted with Ethyl acetate (50.0 mL×3). The combined organiclayers were washed with saturated brine (80.0 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=40/1 to 5:1) The product 1-benzyl 4-tert-butyl(2S)-2-(cyanomethyl)piperazine-1,4-dicarboxylate (18.5 g, 46.4 mmol, twosteps yield 72%) was obtained as a yellow oil. LCMS [ESI, M+1]: 360.

To a solution of 1-benzyl 4-tert-butyl(2S)-2-(cyanomethyl)piperazine-1,4-dicarboxylate (18.5 g, 43.3 mmol,1.00 eq) in dioxane (40.0 mL) was added HCl·dioxane (4 M, 54.1 mL, 5.0eq). The mixture was stirred at 20° C. for 1 hour. Then the reactionmixture was added NaHCO₃ to pH>7, and concentrated under reducedpressure to remove dioxane. The residue was diluted with H₂O (50.0 mL)and extracted with Ethyl acetate (50.0 mL×3). The combined organiclayers were washed with H₂O (20.0 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The productbenzyl (2S)-2-(cyanomethyl)piperazine-1-carboxylate (Intermediate 63,11.5 g, 91.8% purity, 95% yield) was obtained as a yellow oil. LCMS[ESI, M+1]: 260.

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.37-7.31 (m, 5H), 5.14 (s, 2H), 4.49(br, s, 1H), 3.93 (br, s, 1H), 3.07-2.81 (m, 5H), 2.78-2.54 (m, 2H).

Intermediate 64

A mixture of tert-butyl2-methylsulfanyl-4-(trifluoromethylsulfonyloxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(3.81 g, 8.87 mmol, 1.0 eq),benzyl(2S)-2-(cyanomethyl)piperazine-1-carboxylate (Intermediate 63,2.30 g, 8.87 mmol, 1.0 eq), DIEA (3.44 g, 26.6 mmol, 4.63 mL, 3.0 eq) inDMF (20.0 mL) was degassed and purged with N₂ for 3 times, and then themixture was stirred at 100° C. for 1 hour under N₂ atmosphere Aftercompletion, the solvent was removed under vacuum. The residue waspurified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=3/1 to 1.1) to give tert-butyl4-[(3S)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(3.6 g, 6.16 mmol, 69% yield, 92.2% purity) as a yellow solid. LCMS[ESI, M+1]: 539.

A mixture of tert-butyl4-[(3S)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-methylsulfanyl-6,8-dihydro-5Hpyrido[3,4-d]pyrimidine-7-carboxylate(6.0 g, 11.1 mmol, 1.0 eq), TFA (30.8 g, 270 mmol, 20.0 mL, 24.3 eq) inDCM (20.0 mL) was degassed and purged with N₂ for 3 times, and then themixture was stirred at 20° C. for 1 hour under N₂ atmosphere. Aftercompletion, the reaction mixture was quenched with saturated NaHCO₃solution (500 mL). The mixture was extracted with ethyl acetate (3×300mL) and the organic layer was dried over Na₂SO₄ and filtered. Thesolvent was removed under vacuum to give benzyl(2S)-2-(cyanomethyl)-4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(4.8 g, crude) as a yellow solid which was used for the next stepwithout further purification.

A mixture of benzyl(2S)-2-(cyanomethyl)-4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(4.8 g), 1-bromonaphthalene (3.8 g, 18.35 mmol, 2.55 mL), Pd₂(dba)₃ (1.0g, 1.09 mmol), RuPhos (1.02 g, 2.19 mmol) and Cs₂CO₃ (12.0 g, 36.8 mmol)in toluene (30.0 mL) was degassed and purged with N₂ for 3 times, andthen the mixture was stirred at 100° C. for 12 hours under N₂atmosphere. After completion, the reaction mixture was filtered. Theorganic solvent was removed under vacuum to give an oil residue. Theresidue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=5/1 to 3:1) to give benzyl(2S)-2-(cyanomethyl)-4-[2-methylsulfanyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(2.2 g, 3.31 mmol, 85.3% purity, two steps yield 30%) was obtained as ayellow solid. LCMS [ESI, M+1]: 565.

A mixture of benzyl(2S)-2-(cyanomethyl)-4-[2-methylsulfanyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(2.8 g, 3.97 mmol, 1.0 eq), m-CPBA (1.05 g, 5.16 mmol, 1.3 eq) in DCM(4.0 mL) was degassed and purged with N₂ for 3 times, and then themixture was stirred at 0° C. for 1 hour under N₂ atmosphere. Aftercompletion, the reaction is quenched by adding saturated Na₂SO₃ solution(50 mL). The mixture was extracted with ethyl acetate (3×10 mL). Thecombined organic layer was dried with Na₂SO₄ and filtered. The solventwas removed to give a oil residue. The residue was purified by columnchromatography (SiO₂, Methanol/Ethyl acetate=1/20 to 1:10) to givebenzyl(2S)-2-(cyanomethyl)-4-[2-methylsulfinyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(Intermediate 64, 1.5 g, 2.35 mmol, 59% yield, 90.8% purity) as a yellowsolid. LCMS [ESI, M+1]: 581.

Intermediate 65

To a solution of tert-butyl4-[(3S)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(24.3 g, 45.0 mmol, 1.0 eq) in Ethyl acetate (480 mL) was added m-CPBA(8.69 g, 42.8 mmol, 85% purity, 0.95 eq) portionwise at 0° C. Themixture was stirred at 0° C. for 0.5 hour. Upon completion, the mixturewas diluted with water (50.0 mL) and extracted with ethyl acetate (2×300mL). The organic layers were dried over Na₂SO₄ and concentrated undervacuum. The residue was purified by reversed-phase flash [water (0.1%FA)/acetonitrile]. The mixture was neutralized with saturated sodiumbicarbonate solution, concentrated under vacuum to remove MeCN andextracted with ethyl acetate (3×1000 mL). The organic layers were driedover Na₂SO₄ and concentrated under vacuum to give tert-butyl4-[(3S)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(22.8 g, 39.3 mmol, 87% yield, 95.8% purity) as a yellow solid.

¹H NMR (400 MHz, chloroform-d) δ7.37-7.23 (m, 5H), 5.12 (s, 2H),4.75-4.41 (m, 3H), 4.17-4.05 (m, 2H), 3.86 (d, J=11.6 Hz, 1H), 3.81-3.62(m, 1H), 3.46-3.18 (m, 3H), 3.10 (d, J=3.6, 12.0 Hz, 1H), 2.81 (d, J=3.2Hz, 3H), 2.77-2.56 (m, 4H), 1.42 (s, 9H).

To a solution of tert-butyl4-[(3S)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(5.0 g, 9.01 mmol, 1.0 eq) and [(2S)-1-methylpyrrolidin-2-yl]methanol(1.82 g, 15.8 mmol, 1.88 mL, 1.75 eq) in toluene (50.0 mL) was addedt-BuONa (1.73 g, 18.0 mmol, 2.0 eq). The mixture was stirred at 0° C.for 0.5 hour. After completion, the mixture was added cold water (50.0mL) and extracted with ethyl acetate (5×50.0 mL). The combined organiclayer was dried over Na₂SO₄, filtered and concentrated. The obtainedproduct was purified by column chromatography (SiO₂,PE:EA=10:1-EA:MeOH=5:1) to give tert-butyl4-[(3S)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(2.80 g, 4.62 mmol, 51.0% yield) as yellow solid.

¹H NMR (400 MHz, chloroform-d) δ 7.44-7.35 (m, 5H), 5.21 (s, 2H),4.73-4.54 (m, 2H), 4.44-4.33 (m, 2H), 4.22-4.10 (m, 2H), 3.41-3.93 (m,1H), 3.82 (br d, J=11.6 Hz, 2H), 3.39-3.22 (m, 3H), 3.11 (br t, J=7.8Hz, 1H), 2.99 (d, J=3.6, 12.8 Hz, 1H), 2.90-2.56 (m, 5H), 2.49 (s, 3H),2.35-2.25 (m, 1H), 2.07-2.02 (m, 1H), 1.91-1.76 (m, 3H), 1.50 (s, 9H).

To a solution of tert-butyl4-[(3S)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(2.40 g, 3.96 mmol, 1.0 eq) in DCM (8.0 mL) was added TFA (13.9 g, 122mmol, 9.0 mL, 30.7 eq). The mixture was stirred at 15° C. for 2 hours.After completion, the mixture was concentrated. The residue was addedsaturated NaHCO₃ aqueous (20.0 mL) and extracted with DCM (5×10.0 mL).The organic layer was dried over Na₂SO₄, filtered and concentrated. Theproduct benzyl (2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(Intermediate 65, 1.40 g, 2.77 mmol, 70% yield) was obtained as yellowsolid. LCMS [ESI, M+1]: 506.

Intermediate 66

Step A: To a solution of7-benzyl-4-chloro-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(20.0 g, 65.4 mmol, 1 eq) in DCE (200 mL) was added 1-chloroethylcarbonochloridate (28.1 g, 196 mmol, 3 eq) at 0° C. The mixture wasstirred at 0° C. for 30 minutes and 70° C. for 15 hours. The mixture wasconcentrated under vacuum. The residue was dissolved in MeOH (200 mL)and stirred at 70° C. for 0.5 hours. Upon completion, the mixture wasconcentrated under vacuum. The residue was triturated with methyltert-butyl ether (60 mL). The precipitate was collected by filtration,washed with methyl tert-butyl ether (20 mL) and dried under vacuum togive 4-chloro-2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine(17.2 g, crude, HCl) as a yellow solid which was used directly in thenext step without further purification.

¹H NMR (400 MHz, methanol-d₄) δ=4.35 (s, 2H), 3.60 (t, J=6.4 Hz, 2H),3.05 (t, J=6.4 Hz, 2H), 2.55 (s, 3H).

Step B: To a solution of4-chloro-2-methylsulfanyl-5,6,7,8-tetrahydropyrido [3,4-d]pyrimidine(16.5 g, crude, HCl) and TEA (20.0 g, 196 mmol, 27.3 mL) in THF (400 mL)was added benzyl carbonochloridate (16.7 g, 98.1 mmol, 13.9 mL) dropwiseat 0° C. The mixture was stirred at 25° C. for 0.5 hour. Uponcompletion, the mixture was diluted with water (80 mL) and the organiclayer was separated. The aqueous phase was extracted with EtOAc (200mL). The combined organic layers were dried over MgSO₄, filtered andconcentrated under vacuum. The residue was purified by silica gelchromatography (PE/EtOAc 80/1 to 5/1) to give benzyl4-chloro-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (19.6 g, 50.4 mmol, two steps 86% yield,90% purity) as a yellow oil.

¹H NMR (300 MHz, chloroform-d) δ=7.37 (s, 5H), 5.18 (s, 2H), 4.63 (s,2H), 3.877 (d, J=8.0, 2H), 2.80 (br s, 2H), 2.54 (s, 3H).

Step C: To a solution of benzyl4-chloro-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(21.5 g, 55.3 mmol, 1.00 eq) in DMF (400 mL) was added DIEA (35.7 g, 277mmol, 48.2 mL, 5.00 eq) and 2-[(2S)-piperazin-2-yl]acetonitrile (6.92 g,55.3 mmol, 1.00 eq). After stirred at 80° C. for 2 hours, (Boc)₂O (60.4g, 277 mmol, 63.5 mL, 5.00 eq) was added into above mixture and stirredat 80° C. for another 2 hours. Upon completion, the mixture was dilutedwith water (800 mL) and extracted with EtOAc (2×400 mL). The organiclayers were washed with brine (300 mL), dried over Na₂SO₄ andconcentrated under vacuum. The residue was purified by silica gelchromatography (PE/EtOAc 10/1 to 1/1) to give benzyl4-[(3S)-4-tert-butoxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(24.3 g, 43.0 mmol, 78% yield, 95% purity) as a yellow solid.

¹H NMR (400 MHz, chloroform-d) δ=7.43-7.29 (m, 5H), 5.18 (s, 2H),4.76-4.54 (m, 2H), 4.46 (br d, J=18.4 Hz, 1H), 4.08-3.69 (m, 4H),3.53-3.35 (m, 1H), 3.34-3.03 (m, 2H), 3.03-2.89 (m, 1H), 2.81-2.55 (m,4H), 2.50 (s, 3H), 1.51 (s, 9H).

Step D: To a solution of benzyl4-[(3S)-4-tert-butoxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(24.3 g, 45.1 mmol, 1 eq) in EtOAc (480 mL) was added m-CPBA (8.70 g,42.9 mmol, 85% purity, 0.95 eq) potionwise at 0° C. The mixture wasstirred at 0° C. for 0.5 hour. Upon completion, the mixture was dilutedwith water (800 mL). The pH was adjusted to 8 with NaHCO₃ and theorganic layer was separated. The aqueous phase was extracted with EtOAc(2×400 mL). The organic layers were dried over Na₂SO₄ and concentratedunder vacuum. The residue was purified by silica gel chromatography(EtOAc/MeOH 100/1 to 10/1) to give benzyl4-[(3S)-4-tert-butoxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(20.9 g, 36.4 mmol, 81% yield, 96% purity) as a white solid. LCMS [ESI,M+1]: 555.

Step E: To a solution of benzyl4-[(3S)-4-tert-butoxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(20.9 g, 37.6 mmol, 1 eq) and [(2S)-1-methylpyrrolidin-2-yl]methanol(8.67 g, 75.3 mmol, 8.94 mL, 2 eq) in toluene (400 mL) was added t-BuONa(7.23 g, 75.3 mmol, 2 eq) at 0° C. After stirred at 0° C. for 10minutes, the mixture was concentrated under vacuum. The residue wasdiluted with water (200 mL) and extracted with EtOAc (2×400 mL). Theorganic layers were dried over Na₂SO₄ and concentrated under vacuum. Theresidue was purified by reversed-phase flash [water (0.1%FA)/acetonitrile]. The mixture was neutralized with saturated sodiumbicarbonate solution, concentrated under vacuum to remove MeCN andextracted with EtOAc (2×1000 mL). The organic layers were dried overNa₂SO₄ and concentrated under vacuum to give benzyl4-[(3S)-4-tert-butoxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(13.5 g, 20.5 mmol, 54% yield, 92% purity) as a yellow solid. LCMS [ESI,M+1]: 606.

Step F: To a solution of benzyl4-[(3S)-4-tert-butoxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(3.50 g, 5.78 mmol, 1 eq) in MeOH (60.0 mL) was added NH₃/MeOH (60.0mL), Pd/C (1.00 g, 10% purity) under N₂. The suspension was degassedunder vacuum and purged with H₂ several times. The mixture was stirredunder H₂ (15 psi) at 25° C. for 4 hours. Upon completion, the catalystwas filtered off and the filtrate was concentrated under vacuum to givetert-butyl (2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(Intermediate 66, 2.33 g, 4.55 mmol, 79%, 92% purity) as a yellow solidwhich was used directly in the next step without further purification.

¹H NMR (400 MHz, chloroform-d) δ=4.58 (br s, 1H), 4.34 (dd, J=5.2, 10.8Hz, 1H), 4.11 (dd, J=6.8, 10.8 Hz, 1H), 4.08-3.88 (m, 4H), 3.84 (br d,J=12.8 Hz, 1H), 3.25-3.03 (m, 4H), 3.01-2.88 (m, 2H), 2.82-2.51 (m, 5H),2.47 (s, 3H), 2.27 (dt, J=7.2, 9.2 Hz, 1H), 2.11-1.97 (m, 1H), 1.92-1.75(m, 3H), 1.50 (s, 9H).

Intermediate 67

tert-butyl2-methylsulfanyl-4-(trifluoromethylsulfonyloxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate

Step A: tert-butyl4-hydroxy-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate.To a stirred solution of 1-tert-butyl 4-ethyl3-oxopiperidine-1,4-dicarboxylate (50.0 g, 184 mmol, 1.00 eq) in MeOH(1.00 L) at 25° C. under nitrogen was added NaOMe (49.8 g, 921 mmol,5.00 eq), followed by 2-methylisothiourea (62.4 g, 331 mmol, 1.80 eq,H₂SO₄) as a solid. The reaction mixture was stirred at 25° C. for 16hours. The reaction mixture was acidified with HCl (2 M) until pH˜5, andthen the mixture was concentrated under reduced pressure to removedMeOH. The residue was suspended in 300 mL of ethyl acetate and 300 mL ofwater and stirred rapidly. The suspension was filtered and the whitesolid was collected. The filtrate was separated and the organics washedwith water (1×300 mL) and brine (1×200 mL) The organics were isolated,dried over Na₂SO₄, filtered and concentrated to a white solid.tert-butyl4-hydroxy-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(51.0 g, 138 mmol, 75.4% yield, 81% purity) was obtained as a whitesolid and used directly for next step without further purification. LCMS[M+1]: 298.

¹H NMR (400 MHz, chloroform-d) δ: 4.33 (s, 2H), 3.61 (t, J=5.6 Hz, 2H),2.68-2.49 (m, 5H), 1.50 (s, 9H).

Step B: tert-butyl2-methylsulfanyl-4-(trifluoromethylsulfonyloxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate.To a stirred suspension of tert-butyl4-hydroxy-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(51.0 g, 171 mmol, 1.00 eq) in DCM (500 mL) at 0° C. was added DIEA(44.3 g, 343 mmol, 59.9 mL, 2.00 eq), followed by Tf₂O (72.6 g, 257mmol, 42.4 mL, 1.50 eq) under nitrogen. Immediately a brown solutionformed. After stirring at 25° C. for 16 hours, the reaction wasconcentrated to give a brown oil. The brown oil was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=1/0 to 10/1). Titlecompound tert-butyl2-methylsulfanyl-4-(trifluoromethylsulfonyloxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(46.0 g, 107 mmol, 62% yield) was obtained as a yellow solid. LCMS[M+1]: 430.

Intermediate 68

tert-butyl4-[(3S)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate

Step A: tert-butyl4-[(3S)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate.A mixture of tert-butyl2-methylsulfanyl-4-(trifluoromethylsulfonyloxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(3.81 g, 8.87 mmol, 1.0 eq),benzyl(2S)-2-(cyanomethyl)piperazine-1-carboxylate (Intermediate 63,2.30 g, 8.87 mmol, 1.0 eq), DIEA (3.44 g, 26.6 mmol, 4.63 mL, 3.0 eq) inDMF (20.0 mL) was degassed and purged with N₂ for 3 times, and then themixture was stirred at 100° C. for 1 hour under N₂ atmosphere. Aftercompletion, the solvent was removed under vacuum. The residue waspurified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=3/1 to 1:1) to give title compound tert-butyl4-[(3S)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(3.6 g, 6.16 mmol, 69% yield, 92.2% purity) as a yellow solid.

Intermediate 69

1-bromo-8-methylnaphthalene

Step A: 1-bromo-8-methyl-naphthalene. To a solution of1,8-dibromonaphthalene (1 g, 3.50 mmol, 1 eq) in THF (20 mL) was addedMeLi (1.6 M in diethyl ether, 2.62 mL, 1.2 eq) at 0° C. dropwise. Afterstirring for 30 minutes at 0° C., iodomethane (3.38 g, 23.8 mmol, 1.48mL, 6.81 eq) was added dropwise. The mixture was warmed up to 25° C. andstirred for another 3 hours. The reaction mixture was quenched withwater (20 mL) and extracted with ethyl acetate (20 mL×3). The combinedorganic layers were washed with brine (20 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by prep-HPLC (column: Phenomenex Gemini C18 250*50mm*10 um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %:45%-70%, 28 MIN; 40% min). Title compound 1-bromo-8-methyl-naphthalene(340 mg, 1.49 mmol, 43% yield, 97% purity) was obtained as a yellowsolid after lyophilisation.

¹H NMR (400 MHz, chloroform-d) δ=7.75 (dd, J=0.8, 7.2 Hz, 1H), 7.69 (dd,J=0.8, 8.0 Hz, 1H), 7.66-7.59 (m, 1H), 7.30-7.22 (m, 2H), 7.13 (t, J=8.0Hz, 1H), 3.05 (s, 3H).

Intermediate 70

1-bromo-8-chloronaphthalene

Step A: 1H-naphtho[1,8-de][1,2,3]triazine. To a solution ofnaphthalene-1,8-diamine (100 g, 632 mmol, 1 eq) in AcOH (200 mL) andEtOH (1000 mL) was added isoamyl nitrite (72.6 g, 619 mmol, 83.4 mL,0.98 eq) dropwise over a period of 2 h with temperature controlledbetween 18 and 21° C. under a cold-water bath. After the addition, theresulting red suspension was stirred at 25° C. for 16 hours. The solidwas collected by filtration, washed with ethanol (2×500 mL) and driedunder vacuum. Compound 1H-naphtho[1,8-de][1,2,3]triazine (84 g, 496mmol, 79% yield) was obtained as a red crystalline solid and directlyused next step without purification. LCMS [ESI, M+1]: 170.

Step B: 8-chloronaphthalen-1-amine. To a solution of1H-naphtho[1,8-de][1,2,3]triazine (84 g, 496 mmol, 1 eq) in HCl (1.5 L)was added Cu (2.10 g, 33.1 mmol, 234 uL, 0.0665 eq). The mixture wasstirred at 25° C. for 12 hours. The resulting mixture was diluted withwater (500 mL) and heated at 85° C. for 30 mins. The resulting almostclear aqueous solution was filtered, cooled, basified with aqueousammonia (until blue to litmus paper) and the solution was extracted withether acetate (2×1000 mL). The combined extracts were dried over Na₂SO₄.filtered and concentrated under vacuum. The residue was purified bycolumn chromatography (SiO₂, Petroleum ether/Ethyl acetate=200/1 to5/1). Compound 8-chloronaphthalen-1-amine (57 g, 259 mmol, 52% yield,81% purity) was obtained as a red solid. LCMS [ESI, M+1]: 178.

Step C: 1-bromo-8-chloro-naphthalene. To a solution of8-chloronaphthalen-1-amine (57 g, 320 mmol, 1 eq) and TsOH·H₂O (219 g,1.16 mol, 3.6 eq) in MeCN (1000 mL) was added a solution of NaNO₂ (39.8g, 577 mmol, 1.8 eq) and CuBr (138 g, 963 mmol, 29.3 mL, 3 eq) in H₂O(120 mL) at −5° C., then the reaction mixture was stirred at 25° C. for12 hours. The reaction mixture was added saturated Na₂SO₃ solution (100mL) and stirred for 15 mins, then extracted with ethyl acetate (1000mL×3). The combined organic layers were washed with brine (500 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive a residue. The residue was purified by column chromatography (SiO₂,Petroleum ether). Title compound 1-bromo-8-chloro-naphthalene (56 g, 229mmol, 72% yield, 99% purity) was obtained as white solid.

¹H NMR (400 MHz, chloroform-d) δ=7.93 (dd, J=1.2, 7.6 Hz, 1H), 7.82 (dd,J=1.2, 8.4, 1H), 7.79 (dd, J=1.2, 8.4, 1H), 7.67 (dd, J=1.2, 7.6 Hz,1H), 7.37 (t, J=8.0 Hz, 1H), 7.28 (t, J=8.0 Hz, 1H).

Intermediate 71

2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

Step A: 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(0.5 g, 791 umol, 1 eq) in dioxane (5 mL) was added HCl·dioxane (4 M,5.00 mL, 25.3 eq) at 0° C. The mixture was stirred at 25° C. for 1 hour.Upon completion, the mixture was concentrated under vacuum to give animpure product (500 mg, crude, HCl) as a brown solid. 60 mg of theimpure product was purified by prep-HPLC (column: Phenomenex Gemini150*25 mm*10 um; mobile phase: [water (0.04% NH₃·H₂O+10 mMNH₄HCO₃)-ACN]; B % 50%-80%, 10 min). The desired fractions werecollected and lyophilized to give title compound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(19.3 mg, 36.1 umol, 34% purification yield, 99.2% purity) as aoff-white solid. LCMS [ESI, M+1]:532.

¹H NMR (400 MHz, chloroform-d) δ=7.75 (d, J=8.4 Hz, 1H), 7.60 (dd,J=1.6, 8.0 Hz, 1H), 7.52 (dd, J=0.8, 7.2 Hz, 1H), 7.44 (dt, J=3.6, 7.6Hz, 1H), 7.36-7.29 (m, 1H), 7.22 (t, J=6.8 Hz, 1H), 4.46-4.34 (m, 2H),4.15 (td, J=6.4, 10.6 Hz, 1H), 4.04 (br d, J=12.4 Hz, 0.5H), 3.95-3.79(m, 2H), 3.74 (br d, J=12.8 Hz, 0.5H), 3.63-3.48 (m, 1H), 3.40-2.99 (m,7H), 2.98-2.80 (m, 2H), 2.73-2.61 (m, 1H), 2.60-2.49 (m, 3H), 2.47 (d,J=2.4 Hz, 3H), 2.32-2.23 (m, 1H), 2.10-1.99 (m, 1H), 1.82-1.68 (m, 3H).

Intermediate 72

2-[(2S)-4-[7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

Step A:(2S)-2-(cyanomethyl)-4-[7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.A mixture of benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1.22 g, 1.98 mmol, 1.0 eq), 1-bromo-2,3-dimethyl-benzene (1.10 g, 5.93mmol, 802 uL, 3.0 eq), Cs₂CO₃ (1.93 g, 5.93 mmol, 3 eq), RuPhos (185 mg,396 umol, 0.2 eq) and Pd₂(dba)₃ (181 mg, 198 umol, 0.1 eq) in toluene (8mL) was de-gassed and then heated to 90° C. for 12 hours under N₂. Uponcompletion, the mixture was concentrated under vacuum. The residue wasdiluted with water (20 mL) and extracted with EtOAc (3×30 mL). Theorganic layers were dried over Na₂SO₄ filtered and concentrated undervacuum. The residue was purified by reversed-phase flash [water (0.1%FA)/acetonitrile]. The collected desired fractions were neutralized withsaturated aqueous sodium bicarbonate and concentrated under vacuum toremove MeCN, and then extracted with EtOAc (3×50 mL). The organic layerswere dried over Na₂SO₄ and concentrated under vacuum to give(2S)-2-(cyanomethyl)-4-[7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(380 mg, 623 umol, 32% yield, 100% purity) as a yellow solid. LCMS [ESI,M+1]: 610.

Step B:2-[(2S)-4-[7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.NH₃ was bubbled into MeOH (20 mL) at −70° C. for 30 minutes. A solutionof benzyl(2S)-2-(cyanomethyl)-4-[7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(380 mg, 623 umol, 1.0 eq) was added the above solution followed by Pd/C(200 mg, 10% purity) under N₂. The suspension was degassed under vacuumand purged with H₂ several times. The reaction was stirred under H₂ (15psi) at 25° C. for 1 hour Upon completion, the catalyst was filtered andthe filtrate was concentrated to give title compound2-[(2S)-4-[7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(230 mg, 459 umol, 74% yield, 95% purity) as a yellow solid.

¹H NMR (400 MHz, chloroform-d) δ=7.11 (t, J=8.0 Hz, 1H), 6.96 (d, J=8.0Hz, 2H), 4.39 (dd, J=4.8, 10.4 Hz, 1H), 4.14 (dd, J=7.2, 9.6 Hz, 1H),4.02-3.95 (m, 3H), 3.84-3.78 (m, 1H), 3.31-3.19 (m, 1H), 3.17-3.04 (m,5H), 3.04-2.95 (m, 1H), 2.89 (dd, J=9.2, 11.6 Hz, 1H), 2.76-2.62 (m,3H), 2.58-2.50 (m, 2H), 2.48 (s, 3H), 2.30 (s, 3H), 2.29-2.23 (m, 4H),2.12-2.00 (m, 1H), 1.89-1.76 (m, 3H).

Intermediate 73

tert-butyl(2S)-2-(cyanomethyl)-4-[7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

Step A: tert-butyl(2S)-2-(cyanomethyl)-4-[7-(2,3-dimethylphenyl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4d]pyrimidin-4-yl]piperazine-1-carboxylate.A mixture of tert-butyl(2S)-2-(cyanomethyl)-4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(1.60 g, 3.96 mmol, 1.0 eq), 1-bromo-2,3-dimethyl-benzene (1.61 g, 8.70mmol, 1.18 mL, 2.20 eq), Pd₂(dba)₃ (362 mg, 395 umol, 0.10 eq), RuPhos(369 mg, 791 umol, 0.20 eq) and Cs₂CO₃ (3.87 g, 11.9 mmol, 3.0 eq) intoluene (8.0 mL) was degassed and purged with N₂ for 3 times, and thenthe mixture was stirred at 90° C. for 12 hrs under N₂ atmosphere. Theorganic solvent was washed with water (20.0 mL). The aqueous phase wasextracted with ethyl acetate (3×30.0 mL). Combine extracts were washedwith brine (80.0 mL), dried with Na₂SO₄ the solvent was then removedunder vacuum. The residue was purified by column chromatography (SiO₂,Petroleum ether:Ethyl acetate=3:1 to Ethyl acetate:Methanol=10:1).Compound tert-butyl(2S)-2-(cyanomethyl)-4-[7-(2,3-dimethylphenyl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(900 mg, 1.59 mmol, 40% yield, 90% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 509.

¹H NMR (400 MHz, Chloroform-d) δ 7.11 (t, J=15.6 Hz, 1H), 6.95 (d, J=8.0Hz, 2H), 4.63 (br s, 1H), 4.10-3.93 (m, 4H), 3.89 (br d, J=4.8 Hz, 1H),3.27 (dd, J=3.6 Hz, J=13.6 Hz, 1H), 3.24-3.05 (m, 3H), 3.05-2.95 (m,1H), 2.89-2.67 (m, 4H), 2.52 (s, 3H), 2.30 (s, 3H), 2.28 (s, 3H), 1.52(s, 9H).

Step B: tert-butyl(2S)-2-(cyanomethyl)-4-[7-(2,3-dimethylphenyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.A mixture of tert-butyl(2S)-2-(cyanomethyl)-4-[7-(2,3-dimethylphenyl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 983 umol, 1.0 eq), 3-chlorobenzenecarboperoxoic acid (200 mg,983 umol, 1.0 eq) in DCM (5.0 mL) was degassed and purged with N₂ for 3times, and then the mixture was stirred at 0° C. for 30 min under N₂atmosphere. The organic solvent was washed with water (10.0 mL). Theaqueous phase was extracted with ethyl acetate (3×20.0 mL). Combineextracts were washed with brine (50.0 mL), dried with Na₂SO₄ the solventwas then removed under vacuum. The residue was purified by columnchromatography (SiO₂, Petroleum ether:Ethyl acetate=3:1 to Ethylacetate:Methanol=10:1) Compound tert-butyl(2S)-2-(cyanomethyl)-4-[7-(2,3-dimethylphenyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(450 mg, 793 umol, 81% yield, 93% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]:525.

Step C: tert-butyl(2S)-2-(cyanomethyl)-4-[7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.A mixture of tert-butyl(2S)-2-(cyanomethyl)-4-[7-(2,3-dimethylphenyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(800 mg, 1.52 mmol, 1.0 eq) [(2S)-1-methylpyrrolidin-2-yl]methanol (369mg, 3.20 mmol, 380 uL, 2.10 eq), t-BuONa (293 mg, 3.05 mmol, 2.0 eq) intoluene (10.0 mL) was degassed and purged with N₂ for 3 times, and thenthe mixture was stirred at 0° C. for 30 min under N₂ atmosphere. Thereaction was quenched with water (20.0 mL). The crude mixture wasextracted with ethyl acetate (3×30.0 mL). Combine extracts were washedwith brine (80.0 mL), dried with Na₂SO₄ the solvent was then removedunder vacuum. The residue was purged by column chromatography (SiO₂,Petroleum ether:Ethyl acetate=5:1 to Dichloromethane:Methanol=10:1).Title compound tert-butyl(2S)-2-(cyanomethyl)-4-[7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(740 mg, 1.22 mmol, 80% yield, 95% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 576.

¹H NMR (400 MHz, Chloroform-d) δ 7.10 (t, J=15.2 Hz, 1H), 6.95 (d, J=8.0Hz, 2H), 4.61 (br s, 1H), 4.39 (dd, J=4.8 Hz, J=9.6 Hz, 1H), 4.13-4.00(m, 4H), 3.89 (br d, J=12.4 Hz, 1H), 3.27-3.13 (m, 3H), 3.13-2.95 (m,3H), 2.87-2.65 (m, 5H), 2.49 (s, 3H), 2.30 (s, 3H), 2.27 (s, 3H),2.09-2.06 (m, 1H), 2.06-2.04 (m, 1H), 1.93-1.62 (m, 4H), 1.51 (s, 9H).

Example 1

1-(4-(7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: tert-butyl4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:In 2 mL of dimethyl acetamide were combined tert-butyl4-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (1.0 g,3.7 mmol), triethylamine (1.0 mL, 7.4 mmol), and benzyl1-piperazinecarboxylate (0.86 mL, 4.4 mmol). The reaction vessel wassealed and the reaction mixture was heated to 90° C. with stirring.After 5 hours, the reaction was diluted with brine and extracted withmethyl t-butyl ether. The combined organic layers were washedsequentially with saturated ammonium chloride and brine, dried overMgSO₄, and concentrated under reduced pressure to a thick oil. The oilwas chromatographed (RediSep®, 24 g) eluting with 1:1 ethylacetate/Hexanes to give tert-butyl4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(1.3 g, 2.9 mmol, 77% yield). ES+APCI MS m/z 454.2 [M+H]⁺.

Step B: Benzyl4-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:To a solution of tert-butyl4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(1.58 g, 3.484 mmol) in dichloromethane (11.61 mL, 3.484 mmol) was addedtrifluoroacetic acid (2.668 mL, 34.84 mmol) and the reaction was stirredat room temperature for 3 hours. The reaction was concentrated undervacuum and the residue was taken up in dichloromethane. The solution waswashed with sequentially with 1M NaOH and brine, dried over Na₂SO₄,filtered and concentrated under vacuum. The crude product was purifiedby column chromatography (Biotage Isolera, 24G Isco RediSep® Gold, 10 to20% methanol/dichloromethane) to afford the product (1.1 g, 89%) as anoff-white foam. ES+APCI MS m/z 354.2 [M+H]⁺.

Step C: benzyl4(7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:To a vial was added tris(dibenzylideneacetone)dipalladium (0) (0.0069 g,0.0075 mmol), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl(0.0096 g, 0.015 mmol) and toluene (0.62 mL, 0.19 mmol). Argon wasbubbled through the mixture for 5 minutes and then the vial was cappedand the mixture was heated to 100° C. for 15 minutes. The mixture wascooled to ambient temperature and then sodium tert-butoxide (0.036 g,0.37 mmol) was added followed by 1-bromo-3-(methoxymethoxy)naphthalene(0.050 g, 0.19 mmol) and benzyl4-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.13 g, 0.37 mmol). The vial was capped and the mixture heated to 100°C. for 20 hours. The mixture was cooled to ambient temperature, dilutedwith dichloromethane and filtered through GF/F paper. The filtrate wasconcentrated and purified by column chromatography (Biotage Isolera, 12GIsco RediSep®, 10-50% ethyl acetate/dichloromethane) to afford theproduct (0.062 g, 61%) as an off-white foam. ES+APCI MS m/z 540.3[M+H]⁺.

Step D:7-(3-(methoxymethoxy)naphthalen-1-yl)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine:To a solution of benzyl4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.061 g, 0.11 mmol) in ethanol (1.1 mL, 0.11 mmol) and tetrahydrofuran(1.1 mL, 0.11 mmol) was added palladium (0.024 g, 0.011 mmol) (DegussaType, 10 wt. %, 50% H₂O). An atmosphere of H₂ was introduced into thereaction vessel by vacuum, and then the reaction mixture was maintainedunder an atmosphere of H₂. The mixture was stirred at ambienttemperature for 2.5 hours, then diluted with methanol and filteredthrough GF/F paper. The colorless filtrate was concentrated under vacuumwith toluene to provide an off-white foam (0.048 g, 105%) that was useddirectly in the next step. ES+APCI MS m/z 406.2 [M+H]⁺.

Step E:1-(4-(7-(3-(methoxymethoxy)naphthalen-1-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one:To a suspension of7-(3-(methoxymethoxy)naphthalen-1-yl)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine(0.046 g, 0.11 mmol) in dichloromethane (1.1 mL, 0.11 mmol) at ambienttemperature was added acryloyl chloride (1.2 mL, 0.12 mmol) (freshlyprepared 0.1 M solution in dichloromethane) followed by triethylamine(0.032 mL, 0.23 mmol). The reaction was stirred at ambient temperaturefor 1 hour. The mixture was concentrated and the product was purified bycolumn chromatography (Biotage Isolera, 12G Isco RediSep®, ethylacetate) to afford the product (0.042 g, 79%) as an off-white solidfoam. ES+APCI MS m/z 460.2 [M+H]⁺.

Step F:1-(4-(7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one:To a solution of1-(4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one(0.034 g, 0.074 mmol) in ethyl acetate (0.74 mL, 0.074 mmol) was addedhydrochloric acid (5 to 6 N solution in 2-propanol (0.44 mL, 2.2 mmol).The mixture was stirred at ambient temperature for 5 hours. The mixturewas diluted with ethyl acetate (10 mL), filtered through a polypropylenefilter and the collected solid was washed with ethyl acetate and hexanesto provide the product as the HCl salt. The impure material was treatedwith 1 mL of ammonium hydroxide/methanol to quench the acid and themixture was concentrated. The residue was dissolved in 10%methanol/dichloromethane and purified by column chromatography (BiotageIsolera, 12G Isco RediSep®, 2 to 5% methanol/ethyl acetate) to affordthe product (0.008 g, 25%) as an off-white solid. ES+APCI MS m/z 416.2[M+H]⁺.

1H NMR (CD3OD, 400 MHz) δ 8.49 (s, 1H), 8.07 (app d, J=8.2 Hz, 1H), 7.61(app d, J=8.2 Hz, 1H), 7.35 (m, 1H), 7.25 (m, 1H), 6.80 (m, 3H), 6.23(dd, J=16.8, 1.6 Hz, 1H), 5.77 (dd, J=10.6, 2.0 Hz, 1H), 4.22 (br s,2H), 3.80 (app t, J=4.7 Hz, 4H), 3.63 (br s, 4H), 3.35 (br s, 2H), 3.03(br s, 2H).

Example 2

1-(4-(7-(7-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 1, using2-bromo-7-(methoxymethoxy)naphthalene in place of1-bromo-3-(methoxymethoxy)naphthalene in Step C. ES+APCI MS m/z 416.1[M+H]⁺.

Example 3

1-(4-(7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 1, using1-iodonaphthalene in place of 1-bromo-3-(methoxymethoxy)naphthalene inStep C. ES+APCI MS m/z 400.2 [M+H]⁺.

Example 4

1-(4-(7-(2-fluoro-6-hydroxyphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 1, using2-bromo-1-fluoro-3-(methoxymethyl)benzene in place of1-bromo-3-(methoxymethoxy)naphthalene in Step C. ES+APCI MS m/z 384.2[M+H]⁺.

Example 5

1-(4-(7-(2-fluoro-5-hydroxyphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 1, using2-bromo-1-fluoro-4-(methoxymethoxy)benzene in place of1-bromo-3-(methoxymethoxy)naphthalene in Step C. ES+APCI MS m/z 384.2[M+H]⁺.

Example 6

1-(4-(7-(3-hydroxynaphthalen-1-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Steps A-C: benzyl4(7-(3-(methoxymethoxy)naphthalen-1-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:Synthesized according to the method of Example 1, Steps A-C, usingtert-butyl4-chloro-6-methyl-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylatein place of4-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate in Step A.ES+APCI MS m/z 430.2 [M+H]⁺.

Step D1: benzyl4-(7-(3-hydroxynaphthalen-1-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:To a solution of benzyl4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.05 g, 0.09 mmol) in isopropanol (10 mL) was added hydrogen chloride(5-6M in isopropanol) (0.02 mL, 0.09 mmol) and the reaction stirred atroom temperature for 1 hour. The reaction was concentrated under vacuumand the concentrate was partitioned between ethyl acetate and water toconvert the material to the free base. The combined organic layers werewashed with brine, dried over MgSO₄ and concentrated under vacuum togive benzyl4-(7-(3-hydroxynaphthalen-1-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.005 g, 0.010 mmol, 11% yield). ES+APCI MS m/z 510.3 [M+H]⁺.

Step D2:4-(7-(3-hydroxynaphthalen-1-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-ol:Prepared according to the method of Example 1, Step D.

Step E:1-(4-(7-(3-hydroxynaphthalen-1-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one:Prepared according to the method of Example 1, Step E.

Example 7

1-(4-(7-(5-methyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Steps A-D: benzyl4-(7-(5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:Synthesized according to General Scheme 1, Steps A-C, using4-bromo-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole inplace of 1-bromo-3-(methoxymethoxy)naphthalene in Step C.

Step D1: benzyl4-(7-(5-methyl-1H-indazol-4-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:To a solution of benzyl4-(7-(5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.16 g, 0.26 mmol) in dichloromethane (10 mL) was added2,2,2-trifluoroacetic acid (0.89 g, 7.8 mmol) followed by anisole (0.028g, 0.26 mmol), and the reaction was stirred at room temperature for 3hours at room temperature. The reaction was concentrated under vacuumand the concentrated material was taken up in ethyl acetate and washedwith basic brine. The combined organic layers were dried over MgSO₄ andconcentrated under vacuum. The crude material was chromatographed using0 to 10% methanol/dichloromethane as the eluent to give benzyl4-(7-(5-methyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.05 g, 38%). ES+APCI MS m/n 484.2 [M+H]⁺.

Step D2.7-(5-methyl-1H-indazol-4-yl)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine:Prepared according to the method of Example 1, Step D.

Step E:1-(4-(7-(5-methyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one:Prepared according to the method of Example 1, Step E.

Example 8

(S)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: tert-butyl4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:Benzyl 1-piperazinecarboxylate (1.268 mL, 6.575 mmol) and tert-Butyl2,4-dichloro-5,6-dihydropyrido[3 4-d]pyrimidine-7(8H)-carboxylate (2 g,6.575 mmol) were dissolved in dimethyl acetamide (10 mL) and treatedwith N-ethyl-N-isopropylpropan-2-amine (3.445 mL, 19.73 mmol). Thereaction mixture was stirred at 85° C. for 2 hours. The reaction mixturewas cooled to room temperature, diluted with ethyl acetate, washed withwater and brine, dried over MgSO₄, filtered and concentrated. Theconcentrate was purified by chromatography (CombiFiash®, 0%-50% ethylacetate:Hexanes as the eluent to provide the product (2.69 g, 83%).ES+APCI MS m/z 488.2, 490.2 [M+H]⁺.

Step B: tert-butyl(S)-4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-((1-(dimethylamino)propan-2-yl)oxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:Tert-butyl4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(235 mg, 0.482 mmol), and (S)-1-(dimethylamino)propan-2-ol (497 mg, 4.82mmol) were added to dioxane (0.5 mL) and heated to 100° C. for 3 days.The reaction was concentrated and the resulting residue was purified bysilica gel (Biotage Isolera, 0-12% methanol in dichloromethane) toprovide tert-butyl(S)-4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-((1-(dimethylamino)propan-2-yl)oxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(200 mg, 0.361 mmol, 74.9% yield). ES+APCI MS m/z 555.3 [M+H]⁺.

Step C: benzyl(S)-4-(2-((1-(dimethylamino)propan-2-yloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:To a solution of tert-butyl(S)-4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-((1-(dimethylamino)propan-2-yl)oxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(200 mg, 0.3606 mmol) in dichloromethane (1202 μL, 0.3606 mmol) wasadded trifluoroacetic acid (828.3 μL, 10.82 mmol) and the reaction wasstirred at room temperature for 3 hours. The reaction was concentratedunder vacuum and the residue was taken up in dichloromethane. Thesolution was washed with 1M NaOH followed by brine and then dried overNa₂SO₄, filtered and concentrated under vacuum. The crude product waspurified by column chromatography (Biotage Isolera, 24G IscoRediSep®Gold, 10 to 20% methanol/dichloromethane) to afford the productas an off-white foam (0.135 g, 83%). ES+APCI MS m/z 455.2 [M+H]⁺.

Step D: benzyl(S)-4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:To a vial was added tris(dibenzylideneacetone)dipalladium (0) (21.8 mg,0.0238 mmol), racemic-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (30.4mg, 0.0488 mmol) and toluene (991 μL, 0.297 mmol). Argon was bubbledthrough the mixture for 5 minutes and then the vial was capped and themixture was heated to 100° C. for 15 minutes. The mixture was cooled toambient temperature and sodium tert-butoxide (57.2 mg, 0.595 mmol) wasadded followed by 3-(methoxymethoxy)naphthalen-1-yltrifluoromethanesulfonate (100 mg, 0.297 mmol) and benzyl(S)-4-(2-((1-(dimethylamino)propan-2-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(135 mg, 0.297 mmol). The vial was capped and the mixture was heated to100° C. for 18 hours. The mixture was cooled and concentrated. The crudematerial was purified by silica gel (Biotage Isolera, 0-11%methanol/dichloromethane to provide benzyl(S)-4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(68 mg, 0.106 mmol, 35.7% yield). ES+APCI MS m/z 641.3 [M+H]⁺.

Step E:(S)-2-((7-(3-(methoxymethoxy)naphthalen-1-yl)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)-N,N-dimethylpropan-1-amine:To a solution of benzyl(S)-4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(68 mg, 0.11 mmol) in ethanol (1061 μL, 0.11 mmol) and tetrahydrofuran(1061 μL, 0.11 mmol) was added Palladium (113 mg, 0.053 mmol) (DegussaType, 10 wt. %, 50% H₂O). An atmosphere of H₂ was introduced by vacuumand then the reaction vessel was maintained under an atmosphere of H₂.The mixture was stirred at ambient temperature for 3 hours. The mixturewas diluted with methanol and filtered through GF/F paper. The colorlessfiltrate was concentrated to provide(S)-2-((7-(3-(methoxymethoxy)naphthalen-1-yl)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)-N,N-dimethylpropan-1-amine(54 mg, 100% yield) which was used in the next step withoutpurification. ES+APCI MS m/z 507.3 [M+H]⁺.

Step F:(S)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one:To a suspension of(S)-2-((7-(3-(methoxymethoxy)naphthalen-1-yl)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)-N,N-dimethylpropan-1-amine(54 mg, 0.11 mmol) in dichloromethane (1066 μL, 0.11 mmol) at ambienttemperature was added acryloyl chloride (1279 μL, 0.13 mmol)(freshlyprepared 0.1 M solution in DCM) followed by triethylamine (30 μL, 0.21mmol). The reaction was stirred at ambient temperature for 20 minutes.The mixture was concentrated and the product was purified by columnchromatography (Biotage Isolera, 12G Isco RediSep®, 0-15%methanol/dichloromethane) to afford(S)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one(51 mg, 0.091 mmol, 85% yield). ES+APCI MS m/z 561.3 [M+H]⁺.

Step G:1-(4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one:(S)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one(51 mg, 0.091 mmol) was added to a vial containing 350 μL of methanoland a few drops of tetrahydrofuran and the reaction vial was capped. HCl(379 μL, 2.3 mmol) (6M aqueous) was added with stirring, and the mixturewas heated to 55° C. for 3 hours. The reaction was cooled andconcentrated under vacuum. A saturated bicarbonate solution was addedand the reaction was extracted with 10% methanol in dichloromethane. Theorganic layers were combined and concentrated. The resulting residue waspurified by silica gel (Biotage Isolera, 4-20% methanol indichloromethane with 1% concentrated ammonium chloride) to provide thetitle product (25.3 mg, 54%). ES+APCI MS m/z 517.2 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.90 (d, 1H, J=8.314 Hz), 7.54 (d, 1H,J=8.021), 7.34 (m, 1H), 7.24 (m, 1H), 6.72 (m, 1H), 6.56-6.48 (m, 2H),6.32 (dd, 1H, J=16.726, 1.858), 5.73 (dd, 1H, J=10.368, 1.858), 5.45 (m,1H), 4.09-3.94 (m, 2H), 3.63 (bs, 2H), 3.47 (bs, 2H), 3.31 (m, 4H), 3.16(bs, 2H), 2.84 (m, 1H), 2.60 (bs, 2H), 2.45 (m, 1H), 2.43 (s, 6H), 1.31(d, 3H, J=6.162 Hz)

Example 9

1-(4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-(dimethylamino)ethan-1-ol in place of (S)-1-(dimethylamino)propan-2-olin Step B. ES+APCI MS m/z 503.2 [M+H]⁺.

Example 10

1-(4-(2-(3-(dimethylamino)propoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using3-(dimethylamino)propan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 517.3 [M+H]⁺.

Example 11

1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using1-(dimethylamino)propan-2-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 517.3 [M+H]⁺.

Example 12

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using1-methylpiperazine in place of (S)-1-(dimethylamino)propan-2-ol in StepB. ES+APCI MS m/z 514.3 [M+H]⁺.

Example 13

1-(4-(2-(3-(dimethylamino)pyrrolidin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, usingN,N-dimethylpyrrolidin-3-amine in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 528.3 [M+H]⁺.

(S)-1-(4(7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-methylpiperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using benzyl(S)-2-methylpiperazine-1-carboxylate in place of benzylpiperazine-1-carboxylate in Step A and using 2-(dimethylamino)ethan-1-olin place of (S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z517.3 [M+H]⁺.

Example 15

(R)-1-(4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-methylpiperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, substituting benzyl(R)-2-methylpiperazine-1-carboxylate for benzyl piperazine-1-carboxylatein Step A and 2-(dimethylamino)ethan-1-ol for(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 517.3 [M+H]⁺.

Example 16

1-(6-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using benzyl2,6-diazaspiro[3.3]heptane-2-carboxylate in place of benzylpiperazine-1-carboxylate in Step A and substituting2-(dimethylamino)ethan-1-ol in place of (S)-1-(dimethylamino)propan-2-olin Step B. ES+APCI MS m/z 515.3 [M+H]⁺.

Example 17

1-(4-(2-(4-dimethylamino)piperidin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, usingN,N-dimethylpiperidin-4-amine in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 580.3 [M+H]⁺.

Example 18

1-(6-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using benzyl2,6-diazaspiro[3.3]heptane-2-carboxylate in place of benzylpiperazine-1-carboxylate in Step A and substituting1-(dimethylamino)propan-2-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 529.3 [M+H]⁺.

Example 19

(R)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(R)-1-(dimethylamino)propan-2-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 517.3 [M+H]⁺.

1-(6-(2-(3-(dimethylamino)propoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using benzyl2,6-diazaspiro[3.3]heptane-2-carboxylate in place of benzylpiperazine-1-carboxylate in Step A and substituting3-(dimethylamino)propan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 529.3 [M+H]⁺.

Example 21

1-(4-(2-((4-(dimethylamino)butan-2-yl)oxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using4-(dimethylamino)butan-2-od in place of (S)-1-(dimethylamino)propan-2-olin Step B. ES+APCI MS m/z 531.3 [M+]H⁺.

Example 22

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpiperidin-4-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using1-methylpiperidin-4-ol in place of (S)-1-(dimethylamino)propan-2-ol inStep B. ES+APCI MS m/z 529.3 [M+H]⁺.

Example 23

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpyrrolidin-3-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using1-methylpyrrolidin-3-ol in place of (S)-1-(dimethylamino)propan-2-ol inStep B. ES+APCI MS m/z 515.3 [M+H]⁺.

Example 24

1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using1-(dimethylamino)propan-2-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B, using 1-bromo naphthalene inplace of 3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate instep D, and eliminating Step G. ES+APCI MS m/z 501.3 [M+H]⁺.

Example 25

1-(4-(2-(3-(dimethylamino)propoxy)-7-(1-phenylethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using3-(dimethylamino)propan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B, using (1-bromoethyl)benzenein place of 3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonatein step D, and eliminating Step G. ES+APCI MS m/z 559.3 [M+H]⁺.

Example 26

1-(4-(2-(4-(2-hydroxyethyl)piperazin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-(piperazin-1-yl)ethyl acetate in place of(S)-1-(dimethylamino)propan-2-ol in Step B. After Step D, the followingsaponification reaction was performed: Benzyl4-(2-(4-(2-acetoxyethyl)piperazin-1-yl)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatewas taken up in THF (5 mL) and 2 M LiOH (1 mL) was added. The mixturewas stirred at ambient temperature for 24 hr. Saturated NH₄Cl was addedand the reaction was extracted with DCM. The combined organic layerswere concentrated and the resulting residue was purified by silica gel(Biotage Isolera Gold, eluting with 0-10% MeOH in DCM) to provide benzyl4-(2-(4-(2-hydroxyethyl)piperazin-1-yl)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate.The remainder of the synthesis proceeded as in Example 8, step E.ES+APCI MS m/z 544.3 [M+H]⁺.

Example 27

1-((S)-4-(2-(((R)-1-(dimethylamino)propan-2-yl)oxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using benzyl(S)-3-methylpiperazine-1-carboxylate in place of benzylpiperazine-1-carboxylate in Step A and using(R)-1-(dimethylamino)propan-2-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 531.3 [M+H]⁺.

Example 28

(S)-1-(4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using benzyl(S)-3-methylpiperazine-1-carboxylate in place of benzylpiperazine-1-carboxylate in Step A and using 2-(dimethylamino)ethan-1-olin place of (S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z517.2 [M+H]⁺.

Example 29

1(4-(7-(3-hydroxynaphthalen-1-yl)-2-(2-morpholinoethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-morpholinoethan-1-ol in place of (S)-1-(dimethylamino)propan-2-ol inStep B. ES+APCI MS m/z 545.2 [M+H]⁺.

Example 30

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using morpholine inplace of (S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z501.3 [M+H]⁺.

Example 31

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(pyrrolidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using pyrrolidine inplace of (S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z485.2 [M+H]⁺.

Example 32

(R)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-(pyrrolidin-1-yl)propan-2-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(R)-1-(pyrrolidin-1-yl)propan-2-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 543.4 [M+H]⁺.

1-(4-(2-(2-(1,1-dioxidothiomorpholino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-onetrifluoroacetate

Step A: benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a mixture of benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(300 mg, 463.12 μmol, 1.00 eq) and2-(1,1-dioxo-1,4-thiazinan-4-yl)ethanol (166 mg, 926 μmol, 2.00 eq) intoluene (10.0 mL) was added NaOBu-t (133 mg, 1.39 mmol, 3.00 eq), BINAP(57.7 mg, 92.6 μmol, 0.20 eq), Pd₂(dba)₃ (42.4 mg, 46.3 μmol, 0.10 eq).The reaction mixture was stirred at 90° C. for 12 hours under N₂. Thereaction mixture was filtered and the filter cake was washed with DCM(3×10 mL). The filtrate was concentrated under vacuum. The residue waspurified by reverse flash chromatography (40% MeCN in water (0.1% TFA)to give benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(230 mg, 301 μmol, 65.1% yield) as a brown solid. ESI MS m/z 763.5[M+H]⁺.

Step B:4-[2-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol:To a solution of benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(190 mg, 249 μmol, 1.00 eq) in MeOH (10.0 mL) was added Pd/C (100 mg)under N₂. The suspension was degassed under vacuum and purged withhydrogen several times. The mixture was stirred under hydrogen (15 psi)at 40° C. for 4 hours. The reaction mixture was filtered and thefiltrate was concentrated under vacuum to give4-[2-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol(90.0 mg, 167 μmol, 67.1% yield) as a brown solid. ESI MS m/z 539.4[M+H]⁺.

Step C:1-[4-[2-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a solution of4-[2-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol(90.0 mg, 167 μmol, 1.00 eq) and DIEA (64.8 mg, 501 μmol, 87.5 μL, 3.00eq) in DCM (2.00 mL) was added prop-2-enoyl prop-2-enoate (19.0 mg, 150μmol, 0.90 eq) at −40° C. The reaction mixture was stirred at −40° C.for 0.5 h. The reaction mixture was quenched with 1 mL of MeOH andconcentrated under vacuum. The residue was purified by preparative HPLCcolumn: Phenomenex Synergi C18 150*25*, 10μ; mobile phase: [water (0.1%TFA)-ACN]; B %: 12%-42%, 11 min to give1-[4-[2-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-onetrifluoroacetate (32.6 mg, 50.2 μmol, 30.0% yield, 91.3% purity) as abrown solid. ESI MS m/z 593.5 [M+H]⁺.

Example 34

1-(4-(2-(3-(1,1-dioxidothiomorpholino)propoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-onetrifluoroacetate

Synthesized according to the method of Example 33, using3-(1,1-dioxo-1,4-thiazinan-4-yl)propan-1-ol in place of2-(1,1-dioxo-1,4-thiazinan-4-yl)ethanol in Step A. ESI MS m/z 607.5[M+H]⁺.

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(4-morpholinobutoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-onetrifluoroacetate

Synthesized according to the method of Example 33, using4-morpholinobutan-1-ol in place of2-(1,1-dioxo-1,4-thiazinan-4-yl)ethanol in Step A. ESI MS m/z 573.4[M+H]⁺.

Example 36

(R)-1-(4-(2-((1-(4-acetylpiperazin-1-yl)propan-2-yl)oxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 33, using1-[4-[(2R)-2-hydroxypropyl]piperazin-1-yl]ethanone in place of2-(1,1-dioxo-1,4-thiazinan-4-yl)ethanol in Step A. ESI MS m/z 600.6[M+H]⁺.

Example 37

1-(4-(2-(2-(4-acetylpiperazin-1-yl)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: benzyl4-[2-[2-(4-acetylpiperazin-1-yl)ethoxy]-7-(3-benzyloxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of 1-[4-(2-hydroxyethyl)piperazin-1-yl]ethanone (277 mg,1.61 mmol, 2.60 eq) in THF (8.00 mL) was added NaH (49.4 mg, 1.23 mmol,60% purity, 2.00 eq) at 0° C. The reaction mixture was stirred at 0° C.for 15 minutes. To the mixture was addedbenzyl-4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(400 mg, 618 μmol, 1.00 eq) in THF (2.00 mL). The reaction mixture wasstirred at 0° C. for 20 minutes. The reaction mixture was quenched withsaturated NH₄Cl (6 mL) and water (6 mL). The reaction mixture wasextracted with ethyl acetate (3×30 mL). The combined organic layers werewashed with brine (10 mL), dried over Na₂SO₄ and concentrated undervacuum to give benzyl4-[2-[2-(4-acetylpiperazin-1-yl)ethoxy]-7-(3-benzyloxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(450 mg, 534 μmol, 86.5% yield, 89.7% purity) as a brown solid. ESI MSm/z 756.3 [M+H]⁺.

Step B:1-[4-[2-[[7-(3-hydroxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]ethyl]piperazin-1-yl]ethanone:To a solution of benzyl4-[2-[2-(4-acetylpiperazin-1-yl)ethoxy]-7-(3-benzyloxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 264 μmol, 1.00 eq) in THF (10.0 mL) was added Pd/C (100 mg, 10%purity) under N₂. The suspension was degassed under vacuum and purgedwith hydrogen several times. The mixture was stirred under hydrogen (15psi) at 40° C. for 12 hours. The reaction mixture was filtered and thefilter cake was washed with THF (3×5 mL). The filtrate was concentratedunder vacuum to give1-[4-[2-[[7-(3-hydroxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]ethyl]piperazin-1-yl]ethanone(80.0 mg, 150 μmol, 56.9% yield) as a brown solid.

Step C:1-[4-[2-[2-(4-acetylpiperazin-1-yl)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a solution of1-[4-[2-[[7-(3-hydroxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]ethyl]piperazin-1-yl]ethanone(80.0 mg, 150 μmol, 1.00 eq) and DIEA (58.3 mg, 451 μmol, 78.8 μL, 3.00eq) in DCM (2.00 mL) was added prop-2-enoyl prop-2-enoate (14.2 mg, 113μmol, 0.75 eq) at −40° C. for 0.5 h. The reaction mixture was quenchedwith MeOH (1 mL) and diluted by DCM (20 mL) next washed with water (5mL). The combined organic layers were washed with brine (5 mL), driedover Na₂SO₄ and concentrated under vacuum. The reaction mixture waspurified by preparative HPLC: Phenomenex Gemini 150*25 mm*, 10μ; mobilephase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 30%-55%, 10 minto give1-[4-[2-[2-(4-acetylpiperazin-1-yl)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(13.8 mg, 23.3 μmol, 15.5% yield, 98.7% purity) as a yellow solid. ESIMS m/z 586.3 [M+H]⁺.

Example 38

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(3-(piperidin-1-yl)propoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 37, using3-(1-piperidyl)propan-1-ol in place of1-[4-(2-hydroxyethyl)piperazin-1-yl]ethanone in Step A. ESI MS m/z 557.5[M+H]⁺.

Example 39

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(3-(pyrrolidin-1-yl)propoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 37, using3-pyrrolidin-1-ylpropan-1-ol in place of1-[4-(2-hydroxyethyl)piperazin-1-yl]ethanone in Step A. ESI MS m/z 543.3[M+H]⁺.

Example 40

1-(4-(2-(4-(dimethylamino)butoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 37, using4-(dimethylamino)butan-1-ol in place of1-[4-(2-hydroxyethyl)piperazin-1-yl]ethanone in Step A. ESI MS m/z 531.4[M+H]⁺.

Example 41

1-(4-(7-(3-cyclopropyl-5-hydroxyphenyl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-onetrifluoroacetate

Step A:4-[7-(3-benzyloxy-5-cyclopropyl-phenyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a mixture of benzyl4-[2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(400 mg, 805 μmol, 1.00 eq) and1-benzyloxy-3-bromo-5-cyclopropyl-benzene (268 mg, 886 μmol, 1.10 eq) intoluene (10.0 mL) was added2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos) (75.2 mg,161 μmol, 0.20 eq), Pd₂(dba)₃ (111 mg, 121 μmol, 0.15 eq) and Cs₂CO₃(656 mg, 2.01 mmol, 2.50 eq). The reaction mixture was stirred at 90° C.for 12 hours under N₂. The mixture was added to water (15 mL) andextracted with DCM (2×15 mL). The combined organic layers were driedover Na₂SO₄, filtered and concentrated. The residue was purified bychromatography (SiO₂, Petroleum ether/Ethyl acetate=3:1 toDichloromethane:Methanol=10:1) to give benzyl4-[7-(3-benzyloxy-5-cyclopropyl-phenyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(170 mg, 230 μmol, 28.5% yield, 97.2% purity) as brown oil. ESI MS m/z719.6 [M+H]⁺.

Step B:3-cyclopropyl-5-[2-(3-morpholinopropoxy)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]phenol.To a mixture of benzyl4-[7-(3-benzyloxy-5-cyclopropyl-phenyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(150 mg, 209 μmol, 1.00 eq) in MeOH (100 mL) was added Pd/C (150 mg, 10%purity) and CH₃COOH (25.1 mg, 417.3 μmol, 23.9 μL, 2.00 eq). Thesuspension was degassed under vacuum and purged with hydrogen severaltimes. The mixture was stirred under hydrogen (15 Psi) at 40° C. for 2hours. The reaction mixture was filtered through Celite® and thefiltrate was concentrated. The product3-cyclopropyl-5-[2-(3-morpholinopropoxy)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]phenoldiacetate (80.0 mg, 130 μmol, 62.4% yield) was obtained as yellow solid.ESI MS m/z 495.2 [M+H]⁺.

Step C:1-[4-[7-(3-cyclopropyl-5-hydroxy-phenyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one.To a mixture of3-cyclopropyl-5-[2-(3-morpholinopropoxy)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]phenoldiacetate (80.0 mg, 130 μmol, 1.00 eq) in DCM (2.00 mL) was added DIEA(168 mg, 1.30 mmol, 227 μL, 10.0 eq) and prop-2-enoyl prop-2-enoate(13.1 mg, 104 μmol, 0.80 eq) at −78° C., the reaction mixture wasstirred at −78° C. for 0.5 hour. The reaction mixture was quenched withMeOH (2 eq, 10 mg), then concentrated. The residue was purified bypreparative HPLC (Instrument: GX-K; Column: Phenomenex Synergi C18150*25*, 10μ; Conditions: water (0.1% TFA)-ACN; Begin B: 8; End B: 38;Gradient Time (min): 11; 100% B Hold Time (min): 2; FlowRate (mL/min):25). The isolated product was concentrated by lyophilization. Theproduct1-[4-[7-(3-cyclopropyl-5-hydroxy-phenyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-onetrifluoroacetate (21.5 mg, 31.1 μmol, 23.9% yield, 95.8% purity) wasobtained as yellow solid. ESI MS m/z 549.5 [M+H]⁺.

Example 42

1-(4-(7-(2-fluoro-5-hydroxyphenyl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 41, using4-(benzyloxy)-2-bromo-1-fluorobenzene in place of1-benzyloxy-3-bromo-5-cyclopropyl-benzene in Step A. ESI MS m/z 527.4[M+H]⁺.

Example 43

1-(4-(7-(3-hydroxy-6-methylnaphthalen-1-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: benzyl4-[7-(3-methoxy-6-methyl-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.A mixture of benzyl4-[2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 1.01 mmol, 1.00 eq),(3-methoxy-6-methyl-1-naphthyl)trifluoromethanesulfonate (483 mg, 1.51mmol, 1.50 eq), Cs₂CO₃ (820 mg, 2.52 mmol, 2.50 eq),2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos) (93.9 mg,201.3 μmol, 0.20 eq) and Pd₂(dba)₃ (92.2 mg, 100 μmol, 0.10 eq) intoluene (3.00 mL) was stirred at 90° C. for 10 hours. The mixture wasdiluted with ethyl acetate (50.0 mL). The precipitate was removed byfiltration, and the filtrate was concentrated under vacuum. The residuewas purified by reversed phase column chromatography over silica gel(0.1% TFA water/acetonitrile). The desired fractions were combined andbasified with saturated aqueous sodium bicarbonate (2.00 mL), thenconcentrated under vacuum. The residue was extracted with ethyl acetate(2 v 100 mL). The combined extracts were washed with brine (1×100 mL),dried over sodium sulfate, filtered and concentrated under vacuum togive benzyl4-[7-(3-methoxy-6-methyl-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(400 mg, 599 μmol, 59.4% yield, 100% purity) as a yellow solid. ESI MSm/z 667.6 [M+H]⁺.

Step B:4-[3-[[7-(3-methoxy-6-methyl-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propyl]morpholine:To a solution of benzyl4-[7-(3-methoxy-6-methyl-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(370 mg, 554 μmol, 1.00 eq) in MeOH (10.0 mL) was added Pd—C (100 mg,10% purity) and AcOH (66.6 mg, 1.11 mmol, 2.00 eq) under N₂. Thesuspension was degassed under vacuum and purged with hydrogen severaltimes. The mixture was stirred under hydrogen (15 psi) at 40° C. for 2hours. The reaction mixture was filtered and concentrated in vacuum toprovide4-[3-[[7-(3-methoxy-6-methyl-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propyl]morpholine(295 mg, 553 μmol, 99.8% yield) as a yellow solid which was useddirectly in the next step without purification. ESI MS m/z 533.6 [M+H]⁺

Step C:1-[4-[7-(3-methoxy-6-methyl-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a mixture of prop-2-enoyl prop-2-enoate (56.8 mg, 450 μmol, 0.80 eq)and DIEA (727 mg, 5.63 mmol, 983 μL, 10.0 eq) in DCM (2.00 mL) was addeda solution of4-[3-[[7-(3-methoxy-6-methyl-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propyl]morpholine(300 mg, 563 μmol, 1.00 eq) DCM (1.00 mL) at −40° C. under a nitrogenatmosphere. The mixture was stirred for 1 hour. The reaction mixture wasquenched by addition of MeOH (50 μL) at −40° C., diluted with water(10.0 mL), extracted with DCM (10.0 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to provide1-[4-[7-(3-methoxy-6-methyl-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(270 mg, 460 μmol, 81.7% yield) ESI MS m/z 587.6 [M+H]⁺.

Step D:1-[4-[7-(3-hydroxy-6-methyl-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a solution of1-[4-[7-(3-methoxy-6-methyl-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(100 mg, 170 μmol, 1.00 eq) in DCM (3.00 mL) was added BBr₃ (213 mg, 852μmol, 82.1 μL, 5.00 eq) at −78° C. The mixture was stirred at 0° C. for1 hour. The mixture was cooled to −78° C. and diluted with DCM (20.0mL), quenched by addition of saturated sodium bicarbonate solution (5.00mL) and stirred at −78° C. for 10 mins, then warmed to 0° C. The mixturewas extracted with DCM (2×5.0 mL), washed with brine (1×20.0 mL), driedover Na₂SO₄, filtered and concentrated under vacuum. The residue waspurified by preparative HPLC (column: Phenomenex Gemini C18 250*50 mm*,10μ; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %:27%-57%, 12 min) to provide1-[4-[7-(3-hydroxy-6-methyl-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(11.0 mg, 18.6 μmol, 10.9% yield, 97.0% purity) as a brown solid. ESI MSm/z 573.6 [M+H]⁺.

Example 44

1-(4-(7-(5-methyl-1H-indazol-4-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: benzyl4-[7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:A mixture of benzyl4-[2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 1.01 mmol, 1.00 eq), 2-[(4-bromo-5-methyl-indazol-1-yl)methoxy]ethyl-trimethylsilane (448 mg, 1.31 mmol, 1.30 eq), Cs₂CO₁ (822 mg, 2.53mmol, 2.50 eq), Pd₂(dba)₃ (138 mg, 151 μmol, 0.15 eq) and2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos) (94.3 mg,202 μmol, 0.20 eq) in toluene (20.0 mL) was degassed and purged withnitrogen 3 times, and stirred at 90° C. for 10 hours under a nitrogenatmosphere. The reaction mixture was diluted with water (50 mL) andextracted with ethyl acetate (3×100 mL). The combined organic layerswere washed with brine (3×50.0 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byreversed phase HPLC (0.1% TFA water/acetonitrile) to provide benzyl4-[7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(420 mg, 554 μmol, 54.9% yield) as a yellow oil. ESI MS m/z 757.6[M+H]⁺.

Step B: tert-butyl4-[7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of benzyl 4-[7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(370 mg, 488 μmol, 1.00 eq) in MeOH (10.0 mL) was added triethylamine(98.9 mg, 977 μmol, 135 μL, 2.00 eq), Pd/C (100 mg, 10% purity) andtert-butoxycarbonyl tert-butyl carbonate (213 mg, 977 μmol, 224 μL, 2.00eq) under N₂. The suspension was degassed under vacuum and purged withhydrogen several times. The mixture was stirred under hydrogen (15 psi)at 40° C. for 2 hours. The reaction mixture was filtrated andconcentrated under vacuum. The residue was purified by columnchromatography (SiO₂, DCM/MeOH=1:0 to 10:1) to provide tert-butyl4-[7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(340 mg, 470 μmol, 96.2% yield) as a brown oil. ESI MS m/z 723.5 [M+H]⁺.

Step C:4-[3-[[7-(5-methyl-1H-indazol-4-yl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propyl]morpholinetrifluoroacetate: To a solution of tert-butyl4-[7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(150 mg, 207 μmol, 1.00 eq) in DCM (500 μL) was added TFA (354 mg, 3.11mmol, 230 μL, 15.0 eq). The mixture was stirred at 25° C. for 1 hour.The reaction mixture was concentrated in vacuum to provide4-[3-[[7-(5-methyl-1H-indazol-4-yl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propyl]morpholinetrifluoroacetate (125 mg, 206 μmol, 99.3% yield) as a brown oil and useddirectly in the next step without purification. ESI MS m/z 493.4 [M+H]⁺.

Step D1-[4-[7-(5-methyl-1H-indazol-4-yl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a mixture of4-[3-[[7-(5-methyl-1H-indazol-4-yl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propyl]morpholinetrifluoroacetate (120 mg, 197 μmol, 1.00 eq, TFA) and DIEA (255 mg, 1.98mmol, 345 μL, 10.0 eq) in dichloromethane (2.00 mL) was added a solutionof prop-2-enoyl prop-2-enoate (19.9 mg, 158 μmol, 0.80 eq)dichloromethane (1.00 mL) at −40° C. under nitrogen atmosphere. Themixture was stirred for 1 hour. The reaction mixture was quenched byaddition of MeOH (50.0 μL) at −40° C., diluted with water (10.0 mL),extracted with dichloromethane (10.0 mL), dried over Na₂SO₄, filteredand concentrated under reduced pressure. The residue was purified bypreparative HPLC (column: Phenomenex Gemini 150*25 mm*, 10μ; mobilephase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 30%-60%, 10 min)to provide1-[4-[7-(5-methyl-1H-indazol-4-yl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(19.0 mg, 34.4 μmol, 17.4% yield, 99.0% purity) as a white solid. ESI MSm/z 547.5 [M+H]⁺.

Example 45

1-((1R,5S)-3-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one

Step A: tert-butyl3-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate:To a mixture of7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (920 mg,3.13 mmol, 1.00 eq) and tert-butyl3,8-diazabicyclo[3.2.1]octane-8-carboxylate (677 mg, 3.19 mmol, 1.02 eq)in DMSO (18.0 mL) was added DIEA (1.21 g, 9.39 mmol, 1.64 mL, 3.00 eq).The reaction mixture was stirred at 60° C. for 1 hour. The mixture wasdiluted with extracted with EtOAc (3×20 mL), washed with water (10 mL),1N HCl (5 mL), NaHCO₃ (15 mL), and brine (15 mL). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated under vacuum togive tert-butyl3-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(1.30 g, 2.41 mmol, 76.9% yield, 87.0% purity) as a brown oil which wasused directly in the next step without further purification. ESI MS m/z470.2 [M+H]⁺.

Step B: tert-butyl3-[7-benzyl-2-[2-(dimethylamino)-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate:To a solution of 1-(dimethylamino)propan-2-ol (857 mg, 8.31 mmol, 942μL, 3.00 eq) in THF (40.0 mL) was added NaH (222 mg, 5.54 mmol, 60.0%purity, 2.00 eq) at 15° C. under N₂. After stirring at 15° C. for 0.5hour, tert-butyl3-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(1.30 g, 2.77 mmol, 1.00 eq) was added. The mixture was stirred at 100°C. for 12 hours in a sealed tube. The reaction was slowly quenched withwater (3 mL) and then concentrated under vacuum. The residue waspurified by column chromatography (DCM/MeOH 60:1 to 10:1) to givetert-butyl3-[7-benzyl-2-[2-(dimethylamino)-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(700 mg, 1.07 mmol, 38.8% yield, 82.4% purity) as a yellow oil.

Step C: tert-butyl3-[2-[2-(dimethylamino)-1-methyl-ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate:To a solution of tert-butyl3-[7-benzyl-2-[2-(dimethylamino)-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(700 mg, 1.30 mmol, 1.00 eq) in MeOH (30.0 mL) was added Pd/C (200 mg)under N₂. The suspension was degassed under vacuum and purged withhydrogen 4 times. The mixture was stirred under hydrogen (50 psi) at 40°C. for 12 hours. The mixture was concentrated under vacuum. The residuewas purified by column chromatography (DCM/MeOH 50:1 to 5:1) to givetert-butyl3-[2-[2-(dimethylamino)-1-methyl-ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(500 mg, 952 μmol, 73.2% yield, 85.0% purity) as a yellow oil.

Step D: tert-butyl3-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate:Pd₂(dba)₃ (84.1 mg, 91.8 μmol, 0.10 eq) was added to a solution oftert-butyl3-[2-[2-(dimethylamino)-1-methyl-ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(410 mg, 918 μmol, 1.00 eq), 3-benzyloxy-1-bromo-naphthalene (293 mg,936 μmol, 1.02 eq), 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl(RuPhos) (85.7 mg, 184 μmol, 0.20 eq) and Cs₂CO₃ (897 mg, 2.75 mmol,3.00 eq) in dioxane (9.00 mL). The reaction mixture was stirred at 100°C. for 7 hours under N₂ and then concentrated under vacuum. The residuewas diluted with water (5 mL) and extracted with DCM (2×20 mL). Theorganic layers were dried over Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by column chromatography (DCM/MeOH100:1 to 20:1) to give tert-butyl3-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(317 mg, 441 μmol, 48.1% yield, 94.5% purity) as a yellow oil. ESI MSm/z 679.2 [M+H]⁺.

Step E: tert-butyl3-[2-[2-(dimethylamino)-1-methyl-ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate:To a solution of tert-butyl3-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(340 mg, 501 μmol, 1.00 eq) in MeOH (6.80 mL) was added Pd/C (120 mg).The suspension was degassed under vacuum and purged with hydrogen 4times. The mixture was stirred under hydrogen (15 psi) at 40° C. for 1.5hours. The mixture was concentrated under vacuum to give tert-butyl3-[2-[2-(dimethylamino)-1-methyl-ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(210 mg, 316 μmol, 63.1% yield, 88.6% purity) as a yellow solid whichwas used directly in the next step without further purification. ESI MSm/z 589.3 [M+H]⁺.

Step F:4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[2-(dimethylamino)-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-oltrifluoroacetate: To a solution of tert-butyl3-[2-[2-(dimethylamino)-1-methyl-ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(180 mg, 306 μmol, 1.00 eq) in DCM (230 μL) was added TFA (349 mg, 3.06mmol, 226 μL, 10.0 eq). The reaction mixture was stirred at 18° C. for0.5 hour. The mixture was concentrated under vacuum to give4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[2-(dimethylamino)-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-oltrifluoroacetate (528 mg, crude) as a red oil which was used directly inthe next step without further purification. ESI MS m/z 489.2 [M+H]⁺.

Step G:1-[3-[2-[2-(dimethylamino)-1-methyl-ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]prop-2-en-1-one:To a solution of4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[2-(dimethylamino)-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-oltrifluoroacetate (149 mg, 306 μmol, 1.00 eq) and DIEA (1.36 g, 10.5mmol, 1.84 mL, 34.5 eq) in DCM (1.50 mL) was added prop-2-enoylprop-2-enoate (30.9 mg, 245 μmol, 0.80 eq) dropwise at −50° C. Themixture was stirred at −40 and then −20° C. for 30 minutes. The reactionwas quenched with MeOH (19.6 mg) and concentrated under vacuum. Theresidue was purified by preparative TLC (DCM/MeOH 7:1) to give1-[3-[2-[2-(dimethylamino)-1-methyl-ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]prop-2-en-1-one(18.9 mg, 32.8 μmol, 10.7% yield, 94.3% purity) as a yellow solid. ESIMS m/z 543.3 [M+H]⁺.

Example 46

1-((1R,5S)-8-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)prop-2-en-1-one

Synthesized according to the method of Example 4, using tert-butyl(1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate in place tert-butyl3,8-diazabicyclo[3.2.1]octane-8-carboxylate in Step A. ESI MS m/z 543.4[M+H]⁺.

Example 47

1(4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-8-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: ethyl 2-(benzylamino)propanoate: To a solution of ethyl2-bromopropanoate (30.0 g, 165 mmol, 21.6 mL, 1.00 eq), BnNH₂ (23.1 g,215 mmol, 23.6 mL, 1.30 eq) in MeCN (600 mL) was added K₂CO₃ (45.8 g,331 mmol, 2.00 eq). The mixture was stirred at 80° C. for 2 hour. Thereaction mixture was filtered and the filter cake was washed with DCM(300 mL). The filtrated was concentrated under vacuum. The residue waspurified by silica gel chromatography (diethyl ether:ethyl acetate=0.1to 4:1) to give ethyl 2-(benzylamino)propanoate (34.0 g, 163 mmol, 98.4%yield, 99.4% purity) a colorless oil.

Step B: ethyl 4-[benzyl-(2-ethoxy-1-methyl-2-oxo-ethyl)amino]butanoate:To a solution of ethyl 2-(benzylamino)propanoate (31.0 g, 150 mmol, 1.00eq) and ethyl 4-bromobutanoate (87.5 g, 449 mmol, 64.4 mL, 3.00 eq) inMeCN (600 mL) and water (60.0 mL) was added Cs₂CO₃ (97.5 g, 299.12 mmol,2.00 eq) and KI (4.97 g, 29.9 mmol, 0.20 eq). The reaction mixture wasstirred at 80-90° C. for 40 hours. The reaction mixture was filtered andthe filter cake was washed with DCM (2×100 mL). The filtrate wasconcentrated under vacuum. The residue was dissolved in DCM (300 mL) andwashed with brine (80 mL), dried over Na₂SO₄ and concentrated undervacuum. The residue was purified by flash silica gel chromatography(diethyl ether:ethyl acetate=1:0 to 20:1) to give ethyl4-[benzyl-(2-ethoxy-1-methyl-2-oxo-ethyl)amino]butanoate (28.0 g, 87.1mmol, 58.3% yield) as a yellow oil.

Step C: ethyl 1-benzyl-2-methyl-3-oxo-piperidine-4-carboxylate: To asolution of ethyl4-[benzyl-(2-ethoxy-1-methyl-2-oxo-ethyl)amino]butanoate (28.0 g, 87.1mmol, 1.00 eq) in THF (600 mL) was added tBuOK (19.6 g, 174 mmol, 2.00eq). The reaction mixture was stirred at 18° C. for 1 hour. The reactionmixture was quenched with water (100 mL) and extracted with MTBE (3×300mL) and DCM (2×200 mL). The combined organic layers were washed withbine, dried over Na₂SO₄ and concentrated under vacuum. The crude productwas purified by silica gel chromatography (diethyl ether:ethylacetate=100:1 to 20:1) to give ethyl1-benzyl-2-methyl-3-oxo-piperidine-4-carboxylate (20.0 g, 58.8 mmol,67.5% yield, 81.0% purity) as a yellow oil. ESI MS m/z 276.0 [M+H]⁺.

Step D:7-benzyl-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-2,4-diol: ToEtOH (400 mL) was added Na (3.76 g, 163 mmol, 3.88 mL, 2.50 eq). Thereaction mixture was stirred at 20° C. for 0.5 hour. To the mixture wasadded ethyl 1-benzyl-2-methyl-3-oxo-piperidine-4-carboxylate (18.0 g,65.4 mmol, 1.00 eq) and UREA (9.82 g, 163 mmol, 8.77 mL, 2.50 eq) andthe reaction mixture was stirred at 80° C. for 80 hours. The solvent wasremoved under vacuum. The residue was dissolved in water (100 mL) andwashed with MTBE (3×50 mL). The aqueous phase was adjusted to pH 6-7with HCl (15 mL, 12 M). The mixture was filtered and the filter cake waswashed with water (30 mL) and dried in vacuum to give7-benzyl-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-2,4-diol (12.0g, 44.2 mmol, 67.7% yield, 100% purity) was obtained as a brown solid.ESI MS m/z 272.0 [M+H]⁺.

Step E:benzyl-2,4-dichloro-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine: Amixture of7-benzyl-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-2,4-diol (5.00g, 18.4 mmol, 1.00 eq) in POCl₃ (305 g, 1.99 mol, 185 mL, 108 eq) washeated to 110° C. for 12 hours. The solvent was removed under vacuum.The residue was dissolved in DCM (500 mL) and poured into saturatedNaHCO₃ (200 mL) while keeping the pH greater than 7. The organic layerwas washed with brine (50 mL), dried over Na₂SO₄. The solution wasfiltered through a pad of silica gel and the filter cake was washed withDCM (3×400 mL). The combined organic layers were concentrated undervacuum to give7-benzyl-2,4-dichloro-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(4.50 g, 14.6 mmol, 79.2% yield) as a brown oil.

Step F:4-(7-benzyl-2-chloro-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:To a solution of7-benzyl-2,4-dichloro-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(3.00 g, 9.73 mmol, 1.00 eq) and DIEA (2.52 g, 19.5 mmol, 3.40 mL, 2.00eq) in dioxane (60.0 mL) was added tert-butyl piperazine-1-carboxylate(1.90 g, 10.2 mmol, 1.05 eq). The reaction mixture was stirred at 60° C.for 12 hours. The solvent was removed under vacuum. The residue waspurified by silica gel chromatography (diethyl ether:ethyl acetate=2:1)to give tert-butyl4-(7-benzyl-2-chloro-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(3.30 g, 7.15 mmol, 73.5% yield, 99.3% purity) as a yellow solid. ESI MSm/z 458.1 [M+H]⁺.

Step G:tert-butyl-4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of 2-(dimethylamino)ethanol (583 mg, 6.54 mmol, 655 μL,3.00 eq) in toluene (20.0 mL) was added Pd(OAc)₂ (48.9 mg, 218 μmol,0.10 eq),ted-butyl-4-(7-benzyl-2-chloro-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(1.00 g, 2.18 mol, 1.00 eq), Cs₂CO₃ (2.13 g, 6.54 mmol, 3.00 eq) andBINAP (272 mg, 436 μmol, 0.20 eq). The reaction mixture was stirred at110° C. for 3 hours under N₂. The reaction mixture was concentratedunder vacuum. The residue was dissolved in water (10 mL) and extractedwith DCM (3×40 mL). The combined organic layers were washed with brine,dried over Na₂SO₄ and concentrated under vacuum. The residue waspurified by silica gel chromatography (diethyl ether ethyl acetate=5:1to 2:1 then DCM:MeOH=50:1 to 5:1) to givetert-butyl-4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(900 mg, 1.76 mmol, 80.8% yield) as a brown solid. ESI MS m/z 511.2[M+H]⁺.

Step H: tert-butyl4-[2-[2-(dimethylamino)ethoxy]-8-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of tert-butyl4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(800 mg, 1.57 mmol, 1.00 eq) in MeOH (20.0 mL) was added Pd/C (100 mg)under N₂. The suspension was degassed under vacuum and purged withhydrogen several times. The mixture was stirred under hydrogen (50 psi)at 40° C. for 12 hours. The reaction mixture was filtered and the filtercake was washed with MeOH (3×200 mL). The filtrate was concentratedunder vacuum to give tert-butyl4-[2-[2-(dimethylamino)ethoxy]-8-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(450 mg, 1.07 mmol, 68.2% yield) as brown oil which was used for nextstep without further purification. ESI MS m/z 421.3 [M+H]⁺.

Step I: tert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a mixture of tert-butyl4-[2-[2-(dimethylamino)ethoxy]-8-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(380 mg, 904 μmol, 1.00 eq) and 3-benzyloxy-1-bromo-naphthalene (311 mg,994 μmol, 1.10 eq) in dioxane (8.00 mL), Cs₂CO₃ (883 mg, 2.71 mmol, 3.00eq) and 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos)(84.3 mg, 181 μmol, 0.20 eq) and Pd₂(dba)₃ (82.7 mg, 90.4 μmol, 0.10 eq)were added. The reaction mixture was stirred at 90° C. for 12 h underN₂. The reaction mixture was concentrated under vacuum. The residue waspartitioned between DCM (50 mL) and water (20 mL). The reaction mixturewas extracted with DCM (50 mL). The combined organic layers were washedwith brine (10 mL), dried over Na₂SO₄ and concentrated under vacuum. Theresidue was purified by silica gel chromatography (diethyl ether:ethylacetate=5:1 then DCM:MeOH=100:1 to 5:1), followed by purification of theisolated product by preparative TLC (DCM:MeOH=10:1) to give tert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 306 μmol, 33.9% yield) as brown solid. ESI MS m/z 653.4 [M+H]⁺.

Step J:4-[2-[2-(dimethylamino)ethoxy]-8-methyl-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-olbis-trifluoroacetate: To a solution of tert-butyl4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(100 mg, 177 μmol, 1.00 eq) in DCM (130.00 μL) was added TFA (202 mg,1.78 mmol, 132 μL, 10.00 eq). The reaction mixture was stirred at 20° C.for 1 hour. The solvent was removed under vacuum to provide4-[2-[2-(dimethylamino)ethoxy]-8-methyl-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-olbis-trifluoroacetate (175.00 mg) as a brown oil which was used in thenext step without further purification.

Step K:1-[4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a solution of4-[2-[2-(dimethylamino)ethoxy]-8-methyl-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-olbis-trifluoroacetate (97.4 mg, 141 μmol, 1.00 eq) in DCM (500.00 μL) wasadded DIEA (222 mg, 1.72 mmol, 300 μL, 12.2 eq) and prop-2-enoylprop-2-enoate (14.2 mg, 113 μmol, 0.80 eq) at −40° C. The reactionmixture was stirred at −40° C. for 0.5 h. The reaction mixture wasquenched with a drop of MeOH and concentrated under vacuum. The residuewas purified by preparative TLC (DCM:MeOH=10:1) and then by preparativeHPLC (column: Phenomenex Synergi C18 150*25*, 10μ; mobile phase: [water(0.1% TFA)-ACN]; B %: 15%-45% 13 min) to give1-[4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(10.7 mg, 20.7 μmol, three steps 6.8% yield) as a brown oil. ESI MS m/z517.2 [M+H]⁺.

Example 48

1-(4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-onetrifluoroacetate

Step A: ethyl 4-[benzyl-(2-ethoxy-2-oxo-ethyl)amino]pentanoate: Asolution of ethyl 4-oxopentanoate (47.0 g, 326 mmol, 46.5 mL, 1.50 eq),ethyl 2-(benzylamino)acetate (42.0 g, 217.3 mmol, 1.00 eq) and AcOH(13.0 g, 217 mmol, 12.4 mL, 1.00 eq) in DCM (800 mL) was stirred at12-18° C. for 30 min, then cooled at 0-5° C., NaBH(OAc)₃ (138 g, 652mmol, 3.00 eq) was added portion-wise. The mixture was warmed to 10-18°C. and stirred for 16 hours. The reaction mixture was quenched withwater (1000 mL) and extracted with DCM (2×500 mL). The combined organicphases were dried and concentrated to dryness. The residue was purifiedby silica gel column eluting with diethyl ether/ethyl acetate (60:1 to40:1) to provide ethyl 4-[benzyl-(2-ethoxy-2-oxo-ethyl)amino]pentanoate(42.0 g, 91.5 mmol, 42.1% yield, 70% purity) as colorless oil. ESI MSm/z 322.2 [M+H]⁺.

Step B: ethyl 1-benzyl-2-methyl-5-oxo-piperidino-4-carboxylate: Asolution of ethyl 4-[benzyl-(2-ethoxy-2-oxo-ethyl)amino]pentanoate(37.00 g, 115.12 mmol, 1.00 eq) and t-BuOK (16.8 g, 150 mmol, 1.30 eq)in toluene (30.0 mL) was stirred at 25° C. for 5 hours. The reaction wasquenched with water (50 mL) and extracted with ethyl acetate (2×30 mL).The combined organic extracts were dried and concentrated to dryness toprovide ethyl 1-benzyl-2-methyl-5-oxo-piperidine-4-carboxylate (14.6 g,53.0 mmol, 46% yield) as yellow oil which was used directly in the nextstep.

Step C:7-benzyl-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-2,4-diol: Na(3.05 g, 133 mmol, 3.14 mL, 2.50 eq) was dissolved in EtOH (280 mL), andthen ethyl 1-benzyl-2-methyl-5-oxo-piperidine-4-carboxylate (14.6 g,53.0 mmol, 1.00 eq) and urea (7.96 g, 133 mmol, 7.11 mL, 2.50 eq) wereadded. The reaction mixture was heated to reflux (78° C.) for 16 hrsunder N₂. The reaction mixture was concentrated to dryness. The residuewas dissolved in water (100 mL), washed with MTBE (100 mL). The pH ofthe water phase was adjusted to pH 6-7 with 6N HCl (2 mL). The resultingsolid was collected by filtration and dried under vacuum at 60° C. toprovide7-benzyl-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-2,4-diol (5.00g, 17.1 mmol, 32.3% yield, 93% purity) as light yellow solid.

Step D:7-benzyl-2,4-dichloro-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine:POCl₃ (49.5 g, 323 mmol, 30.0 mL, 58.4 eq) and7-benzyl-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-2,4-diol (1.50g, 5.53 mmol, 1.00 eq) were heated to 100° C. under reflux for 12 hours.The reaction was concentrated to dryness to remove POCl₃. The residuewas dissolved in DCM (40 mL) and washed with saturated NaHCO₃aqueous/saturated aqueous Na₂CO₃ (1/1, 60 mL). The mixture was filteredand the organic layers were dried over Na₂SO₄, filtered and concentratedunder vacuum to give7-benzyl-2,4-dichloro-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(2.08 g, crude) as a brown solid which was used directly in the nextstep without further purification. ESI MS m/z 307.9, 309.9 [M+H]⁺.

Step E:4-(7-benzyl-2-chloro-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:To a mixture of7-benzyl-2,4-dichloro-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(2.50 g, 8.11 mmol, 1.00 eq) and tert-butyl piperazine-1-carboxylate(1.54 g, 8.27 mmol, 1.02 eq) in dioxane (50.0 mL) was added DIEA (3.14g, 24.3 mmol, 4.25 mL, 3.00 eq). The mixture was stirred at 60° C. for20 hours. The mixture was concentrated under vacuum. The residue wasdiluted with water (20 mL) and extracted with DCM (2×80 mL). The organiclayers were dried over Na₂SO₄ and concentrated under vacuum. The residuewas purified by automated flash chromatography system (diethylether/ethyl acetate 50:1 to 2:1) to give tert-butyl4-(7-benzyl-2-chloro-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(2.59 g, 5.29 mmol, 65.2% yield, 93.5% purity) as a yellow solid.

Step F: tert-butyl4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of 2-(dimethylamino)ethanol (701 mg, 7.86 mmol, 788 μL,3.00 eq) in THF (45.0 mL) was added NaH (210 mg, 5.24 mmol, 60.0%purity, 2.00 eq) at 15° C. under N₂. After stirring at 15° C. for 0.5hour, tert-butyl4-(7-benzyl-2-chloro-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(1.20 g, 2.62 mmol, 1.00 eq) was added. The mixture was stirred at 110°C. for 18 hours in a sealed tube. The mixture was concentrated undervacuum. The residue was purified by column chromatography over Al₂O₃(DCM/MeOH 100:1 to 10:1) to give tert-butyl4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1.38 g, 2.36 mmol, 90.3% yield, 87.5% purity) as a yellow oil. ESI MSm/z 511.3 [M+H]⁺.

Step G: tert-butyl4-[2-[2-(dimethylamino)ethoxy]-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of tert-butyl4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1.50 g, 2.94 mmol, 1.00 eq) in MeOH (80.0 mL) was added Pd/C (450 mg)under N₂. The suspension was degassed under vacuum and purged withhydrogen 4 times. The mixture was stirred under hydrogen (50 psi) at 40°C. for 12 hours. The reaction mixture was filtered and the filtrate wasconcentrated. The residue was purified by column chromatography(DCM/MeOH 40/1 to 10/1) to give tert-butyl4-[2-[2-(dimethylamino)ethoxy]-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1.15 g, 2.46 mmol, 83.7% yield, 90.0% purity) as a yellow oil.

Step H: tert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:Pd₂(dba)₃ (109 mg, 119 μmol, 0.10 eq) was added to a solution oftert-butyl4-[2-[2-(dimethylamino)ethoxy]-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 1.19 mmol, 1.00 eq), 3-benzyloxy-1-bromo-naphthalene (410 mg,1.31 mmol, 1.10 eq), 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl(RuPhos) (111 mg, 238 μmol, 0.20 eq) and Cs₂CO₃ (1.16 g, 3.57 mmol, 3.00eq) in dioxane (10.0 mL). The reaction mixture was stirred at 90° C. for12 hours under N₂. The mixture was concentrated under vacuum. Theresidue was diluted with water (5 mL) and extracted with DCM (2×20 mL).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by columnchromatography over Al₂O₃(DCM/MeOH 100/1 to 10/l) and by preparative TLC(DCM/MeOH 5:1) to give tert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(309 mg, 453 μmol, 38.1% yield, 95.8% purity) as a yellow oil.

Step I: tert-butyl4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of tert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(340 mg, 521 μmol, 1.00 eq) in MeOH (6.80 mL) was added Pd/C (120 mg)under N₂. The suspension was degassed under vacuum and purged withhydrogen 4 times. The mixture was stirred under hydrogen (15 psi) at 40°C. for 1.5 hours. The mixture was concentrated under vacuum to givetert-butyl4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(210 mg, 312 μmol, 59.8% yield, 83.5% purity) as a pink solid which wasused directly in the next step without further purification. ESI MS m/z563.3 [M+H]⁺.

Step J:4-[2-[2-(dimethylamino)ethoxy]-6-methyl-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-oltrifluoroacetate: To a solution of tert-butyl4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(180 mg, 320 μmol, 1.00 eq) in DCM (240 μL) was added TFA (365 mg, 3.20mmol, 237 μL, 10.0 eq). The mixture was stirred at 18° C. for 0.5 hour.The mixture was concentrated under vacuum to give4-[2-[2-(dimethylamino)ethoxy]-6-methyl-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-oltrifluoroacetate (273 mg) as a yellow oil which was used directly in thenext step without further purification.

Step K.1-[4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a solution of4-[2-[2-(dimethylamino)ethoxy]-6-methyl-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-oltrifluoroacetate (148 mg, 320 μmol, 1.00 eq) and DIEA (494 mg, 3.83mmol, 668 μL, 12.0 eq) in DCM (500 μL) was added prop-2-enoylprop-2-enoate (32.3 mg, 256 μmol, 0.80 eq) dropwise at −50° C. Themixture was stirred at −40 to −20° C. for 30 minutes. The reaction wasquenched with MeOH (20.5 mg) and concentrated under vacuum. The residuewas purified by preparative HPLC (column: Phenomenex Synergi C18150*25*, 10μ; mobile phase: [water (0.1% TFA)-ACN]; B %: 8%-38%, 13 min)to give1-[4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-onetrifluoroacetate (73.7 mg, 113 μmol, 35.2% yield, 96.3% purity) as ayellow solid. ESI MS m/z 517.3 [M+H]⁺.

Example 49

1-(4-(2-(2-(3-fluoropyrrolidin-1-yl)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-[2-(3-fluoropyrrolidin-1-yl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate:A mixture of 2-(3-fluoropyrrolidin-1-yl)ethanol (401 mg, 3.01 mmol, 1.60eq), tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-methylsulfonyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(1.00 g, 1.88 mmol, 1.00 eq), Cs₂CO₃ (1.84 g, 5.64 mmol, 3.00 eq),Pd(OAc)₂ (42.2 mg, 188 μmol, 0.10 eq) and BINAP (234 mg, 376 μmol, 0.20eq) in toluene (50.00 mL) was stirred at 110° C. for 3 hours. Themixture was concentrated under vacuum. The residue was purified bycolumn chromatography over silica gel (petroleum ether/ethyl acetate10:1 to 100:1). The desired fractions were collected and concentratedunder vacuum to give tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-[2-(3-fluoropyrrolidin-1-yl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(1.20 g, 1.07 mmol, 56.8% yield, 52% purity) as a yellow solid. ESI MSm/z 585.3 [M+H]⁺.

Step B: benzyl4-[2-[2-(3-fluoropyrrolidin-1-yl)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-[2-(3-fluoropyrrolidin-1-yl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(1.20 g, 2.05 mmol, 1.00 eq) in DCM (10.00 mL) was added TFA (3.51 g,30.8 mmol, 2.28 mL, 15.00 eq) at 0° C. The mixture was warmed to 25° C.and stirred for 16 hours. The mixture was diluted with water (100 mL)and the solution was extracted with ethyl acetate (2>100 mL). The waterlayer was basified with saturated aqueous sodium carbonate solution (50mL) and then extracted with ethyl acetate (2×100 mL). The combinedorganic layers were washed with brine (1×100 mL), dried over sodiumsulfate, and filtered. The filtrate was concentrated under vacuum toprovide benzyl4-[2-[2-(3-fluoropyrrolidin-1-yl)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate (800 mg, 1.65 mmol, 80.4%yield) as a yellow gum. ESI MS m/z 485.3 [M+H]⁺.

Step C: benzyl4-[2-[2-(3-fluoropyrrolidin-1-yl)ethoxy]-7-(3-methoxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:A mixture of benzyl4-[2-[2-(3-fluoropyrrolidin-1-yl)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(750 mg, 1.55 mmol, 1.00 eq), (3-methoxy-1-naphthyl)trifluoromethanesulfonate (949 mg, 3.10 mmol, 2.00 eq),2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos) (144.66 mg,310.00 μmol, 0.20 eq), Pd₂(dba)₃ (141.94 mg, 155.00 μmol, 0.10 eq) andCs₂CO₃ (1.52 g, 4.65 mmol, 3.00 eq) in toluene (70.00 mL) was stirred at110° C. for 16 hours. The mixture was concentrated under vacuum and thendiluted with ethyl acetate (100 mL) and water (100 mL). The separatedorganic layer was washed with brine (1×100 mL), dried over sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography over silica gel (petroleum ether/ethylacetate 10:1 to ethyl acetate/methanol 10:1). The desired fractions werecollected and concentrated under vacuum to give benzyl4-[2-[2-(3-fluoropyrrolidin-1-yl)ethoxy]-7-(3-methoxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(700 mg, 961 μmol, 62.0% yield, 88% purity) as a brown solid. ESI MS m/z641.3 [M+H]⁺.

Step D:2-[2-(3-fluoropyrrolidin-1-yl)ethoxy]-7-(3-methoxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine:A mixture of benzyl4-[2-[2-(3-fluoropyrrolidin-1-yl)ethoxy]-7-(3-methoxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(700.00 mg, 1.09 mmol, 1.00 eq) in MeOH was hydrogenated (15 psi) at 40°C. with dry Pd/C (140 mg,) as a catalyst for 4 hours. The catalyst wasfiltered through a Celite® pelt and the filtrate was concentrated undervacuum to provide2-[2-(3-fluoropyrrolidin-1-yl)ethoxy]-7-(3-methoxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(500 mg, 987 μmol, 90.6% yield) as a brown solid.

Step E:1-[4-[2-[2-(3-fluoropyrrolidin-1-yl)ethoxy]-7-(3-methoxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a mixture of2-[2-(3-fluoropyrrolidin-1-yl)ethoxy]-7-(3-methoxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(500 mg, 987 μmol, 1.00 eq) and DIEA (255 mg, 1.97 mmol, 345 μL, 2.00eq) in dichloromethane (8 mL) was added a solution of prop-2-enoylprop-2-enoate (124 mg, 987 μmol, 1.00 eq) in dichloromethane (2 mL) at−40° C. under nitrogen atmosphere. The mixture was warmed to 25° C. andstirred for 1 hour. The mixture was diluted with water (20 mL) anddichloromethane (30 mL). The separated organic layer was washed withbrine (1×30 mL), dried over magnesium sulfate, filtered and concentratedunder vacuum. The residue was purified by column chromatography oversilica gel (dichloromethane/methanol 100/1 to 10/1). The desiredfractions were collected and concentrated under vacuum to give1-[4-[2-[2-(3-fluoropyrrolidin-1-yl)ethoxy]-7-(3-methoxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(450 mg, 714 μmol, 72.4% yield, 89% purity) as a yellow solid. ESI MSm/z 561.2 [M+H]⁺.

Step F:1-[4-[2-[2-(3-fluoropyrrolidin-1-yl)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a solution of 1-[4-[2-[2-(3-fluoropyrrolidin-1-yl)ethoxy]-7-(3-methoxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(400 mg, 713 μmol, 1.00 eq) in DCM (2.00 mL) was added BBr₃ (1.30 g,5.19 mmol, 500 μL, 7.27 eq) at −70° C. under nitrogen atmosphere. Themixture was warmed to 0° C. and stirred for 1 hour. The mixture wasdiluted with dichloromethane (20 mL), and then quenched with saturatedaqueous sodium bicarbonate solution (20 mL). The separated organic layerwas washed with brine (1×10 mL), dried over sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by preparative HPLC(Phenomenex Synergi C18 150*25*, 10μ; mobile phase: [water (0.1%TFA)-ACN]; B %: 18%-48%, 12 min.) The desired fractions were collectedand lyophilized to give1-[4-[2-[2-(3-fluoropyrrolidin-1-yl)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(40.0 mg, 63.7 μmol, 8.92% yield, 87% purity) was a yellow solid. ESI MSm/z 547.3 [M+H]⁺.

Example 50

1-(4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(hydroxymethyl)piperazin-1-yl)prop-2-en-1-one

Step A: 1-tert-butyl2-methyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1,2-dicarboxylate:To a solution of 7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (2.00 g, 6.80 mmol, 1.00 eq) in DMSO (40.0 mL) was added DIEA(1.76 g, 13.6 mmol, 2.38 mL, 2.00 eq) and 1-tert-butyl2-methylpiperazine-1,2-dicarboxylate (1.74 g, 7.14 mmol, 1.05 eq). Themixture was stirred at 55° C. for 16 hours. The mixture was diluted withwater (100 mL) and extracted with ethyl acetate (3×100 mL). The combinedorganic layers were washed with brine (3×100 mL), dried over Na₂SO₄,filtered and concentrated to dryness. The residue was purified by columnchromatography (SiO₂, diethyl ether/ethyl acetate=1:0 to 3:1) to give1-tert-butyl2-methyl-4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1,2-dicarboxylate(3.10 g 5.70 mmol, 83.8% yield, 92.3% purity) as a yellow semisolid. ESIMS m/z 502.2 [M+H]⁺.

Step B: 1-tert-butyl2-methyl4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate: A mixture of 1-tert-butyl2-methyl-4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1,2-dicarboxylate(3.00 g, 5.98 mmol, 1.00 eq), 2-(dimethylamino)ethanol (1.07 g, 12.0mmol, 1.20 mL, 2.00 eq), Cs₂CO₃ (4.87 g, 15.0 mmol, 2.50 eq), Pd(OAc)₂(201 mg, 897 μmol, 0.15 eq) and BINAP (744 mg, 1.20 mmol, 0.20 eq) intoluene (60.0 mL) was degassed and purged with nitrogen 3 times, andthen the mixture was stirred at 110° C. for 3 hours under a nitrogenatmosphere. The reaction mixture was diluted with water (50 mL) andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with brine (3×50 mL), dried over Na₂SO₄, filtered andconcentrated to dryness. The residue was purified by columnchromatography (SiO₂, DCM/MeOH=1:0 to 5.1) to give 1-tert-butyl2-methyl-4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate (3.10 g, 4.45 mmol, 80.4%yield, 86.0% purity) as a black oil. ESI MS m/z 555.3 [M+H]⁺.

Step C: 1-tert-butyl2-methyl4-[2-[2-dimethylamino)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate:To a solution of 1-tert-butyl2-methyl-4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate(2.33 g, 4.20 mmol, 1.00 eq) in MeOH (50.0 mL) was added Pd/C (233 mg)under N₂. The suspension was degassed under vacuum and purged withhydrogen several times. The mixture was stirred under hydrogen (50 psi)at 40° C. for 36 hours. The reaction mixture was filtered and theorganic phase was concentrated to dryness to give1-tert-butyl-2-methyl4-[2-[2-(dimethylamino)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate(1.50 g, crude) as a colorless oil, which was used directly in the nextstep without further purification.

Step D: 1-tert-butyl2-methyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate:A mixture of1-tert-butyl-2-methyl4-[2-[2-(dimethylamino)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate(1.50 g, crude), 3-benzyloxy-1-bromo-naphthalene (1.49 g, 4.76 mmol,1.30 eq), Cs₂CO₃ (2.98 g, 9.15 mmol, 2.50 eq), Pd₂(dba)₃ (503 mg, 549μmol, 0.15 eq) and 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl(RuPhos) (342 mg, 732 μmol, 0.20 eq) in dioxane (100 mL) was degassedand purged with nitrogen 3 times, and the mixture was stirred at 85° C.for 5 hours under a nitrogen atmosphere. The reaction mixture wasquenched by adding water (50 mL) at 0° C., and extracted with DCM (3×100mL). The combined organic layers were washed with brine (3×150 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure todryness. The residue was purified by column chromatography (SiO₂,DCM/MeOH=10:1 to 5:1) to give 1-tert-butyl2-methyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate(1.72 g, 2.25 mmol, 53.5% yield, 91% purity) as a yellow. ESI MS m/z697.3 [M+H]⁺.

Step E: methyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-2-carboxylate: To asolution of 1-tert-butyl2-methyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate(1.32 g, 1.89 mmol, 1.00 eq) in DCM (20.0 mL) was added TFA (4.31 g,37.8 mmol, 2.80 mL, 20.0 eq) at 0° C. and the reaction mixture wasstirred for 2 hours at 25° C. The reaction mixture was concentratedunder reduced pressure to dryness. The residue was dissolved in DCM (50mL) and 1120 (20 mL) and the reaction mixture was adjusted to pH 8 withsaturated NaHCO₃. The organic layer was dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give methyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-2-carboxylate(1.12 g, 1.87 mmol, 69.6% yield, 70% purity) as a brown oil, which wasused directly in the next step without further purification. ESI MS m/z597.4 [M+H]⁺.

Step F:[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]methanol:A mixture ofmethyl-4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-2-carboxylate(400 mg, 0.670 mmol) in THF (5.00 mL) was added LiAlH₄ (102 mg, 2.68mmol, 4.00 eq) at 0° C. The reaction mixture was degassed and purgedwith nitrogen 3 times, and stirred at 0° C. for 2 hours under a nitrogenatmosphere. The reaction mixture was quenched by addition ofNa₂SO₄.10H₂O (0.5 g) at 0° C., and then diluted with DCM (50 mL). Thecombined organic layers were filtered, dried over Na₂SO₄, andconcentrated under reduced pressure to give[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]methanol(280 mg, 0.493 mmol, 73.6% yield) as a yellow semisolid, which was useddirectly in the next step without further purification ESI MS m/z 569.3[M+H]⁺.

Step G:2-[[7-(3-benzyloxy-1-naphthyl)-4-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]-N,N-dimethyl-ethanamine:To a stirred solution of[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]methanol(250 mg, 440 μmol, 1.00 eq) and NaH (176 mg, 4.40 mmol, 60.0% purity,10.0 eq) in THF (10.0 mL) was added tert-butyldimethylsilyl chloride(232 mg, 1.54 mmol, 189 μL, 3.50 eq) at 0° C. The mixture was stirred at25° C. for 12 hours under a nitrogen atmosphere. The reaction mixturewas quenched by addition of water (25 mL) at 0° C. and extracted withDCM (3×30 mL). The combined organic layers were washed with brine (3×30mL), dried over Na₂SO₄, filtered and concentrated under reduced pressureto dryness. The residue was purified by preparative TLC (SiO₂,DCM/MeOH=10:1) to give2-[[7-(3-benzyloxy-1-naphthyl)-4-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]-N,N-dimethyl-ethanamine(128 mg, 180 μmol, 40.9% yield, 96.0% purity) as a colorless semisolid.ESI MS m/z 683.3 [M+H]⁺.

Step H: 1-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-[[tert-butyl(dimethyl)silyl]oxymethyl]piperazin-1-yl]prop-2-en-1-one;To a solution of 2-[[7-(3-benzyloxy-1-naphthyl)-4-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]-N,N-dimethyl-ethanamine(128 mg, 187 μmol, 1.00 eq) and triethylamine (47.4 mg, 469 μmol, 65.0μL, 2.50 eq) in DCM (5.00 mL) was added prop-2-enoyl prop-2-enoate (35.5mg, 281 μmol, 1.50 eq) dropwise at −40° C. and stirred for 30 minutes.The reaction mixture was concentrated under reduced pressure to dryness.The residue was purified by preparative TLC (SiO₂, DCM/MeOH=10:1) togive 1-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-[[tert-butyl(dimethyl)silyl]oxymethyl]piperazin-1-yl]prop-2-en-1-one(92.0 mg, 101 μmol, 54.0% yield, 81.0% purity) as a yellow solid. ESI MSm/z 737.3 [M+H]⁺.

Step I:1-[4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(hydroxymethyl)piperazin-1-yl]prop-2-en-1-one:A mixture of 1-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-[[tert-butyl(dimethyl)silyl]oxymethyl]piperazin-1-yl]prop-2-en-1-one(92.0 mg, 125 μmol, 1.00 eq) in DCM (8.00 mL) was added BBr₃ (17.0 mg,67.8 μmol, 6.53 μL, 10.0 eq). The mixture was stirred at −40° C. for 30minutes under a nitrogen atmosphere and then concentrated at 25° C.under reduced pressure to dryness. To the residue was added saturatedNaHCO₃ aqueous (0.5 mL). The solution was adjusted to pH 7 at 0° C. andthen MeOH (2.0 mL) was added. The solution was purified by preparativeHPLC (column: Phenomenex Synergi C18 150*25*, 10μ; mobile phase: [water(0.1% TFA)-ACN]; B %: 15%-45%, 11 min). The desired fractions werecollected and concentrated under reduced pressure to remove MeCN andlyophilized to give1-[4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(hydroxymethyl)piperazin-1-yl]prop-2-en-1-one(6.30 mg, 11.2 μmol, 9.00% yield, 95.0% purity) as a yellow solid. ESIMS m/z 533.2 [M+H]⁺.

Example 51

1-acryloyl-4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N,N-dimethylpiperazine-2-carboxamide

Step A:4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-tert-butoxycarbonyl-piperazine-2-carboxylicacid: To a solution of 1-tert-butyl 2-methyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate(300 mg, 431 μmol, 1.00 eq) in THF (4.00 mL) and H2O (1.00 mL) was addedNaOH (68.9 mg, 1.72 mmol, 4.00 eq). The mixture was stirred at 25° C.for 12 hours under a nitrogen atmosphere. The reaction mixture wasdiluted with water (50 mL) and the reaction mixture was adjusted to pH 6with HCl (6 M) and then extracted with DCM (3×50 mL). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated underreduced pressure to dryness to give4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-tert-butoxycarbonyl-piperazine-2-carboxylicacid (310 mg, crude) as a yellow solid which was used directly in thenext step without further purification. ESI MS m/z 683.3 [M+H]⁺.

Step B:tert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(dimethylcarbamoyl)piperazine-1-carboxylateA mixture of4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-tert-butoxycarbonyl-piperazine-2-carboxylicacid (310 mg, crude) and DIEA (352 mg, 2.72 mmol, 476 μL) in DCM (10.0mL) was added portionwise HATU (259 mg, 681 μmol) at 0° C. Afterstirring for 30 minutes, N-methylmethanamine (130 mg, 1.59 mmol, 146 μL,HCl) was added in one portion. The reaction mixture was degassed andpurged with nitrogen 3 times. After stirring at 25° C. for 12 hoursunder a nitrogen atmosphere, the reaction mixture was diluted with water(50 mL) at 0° C. and extracted with DCM (3×50 mL). The combined organiclayers were adjusted to pH 6 with HC (1 M), washed with brine (3×50 mL)and water (3×50 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to dryness to givetert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(dimethylcarbamoyl)piperazine-1-carboxylate(345 mg, 428 μmol, two steps 94.2% yield, 88.0% purity) as a yellowsemi-solid. ESI MS m/z 710.3 [M+H]⁺.

Step C: tert-butyl4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(dimethylcarbamoyl)piperazine-1-carboxylate: Toa solution of tert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(dimethylcarbamoyl)piperazine-1-carboxylate(345 mg, 486 μmol, 1.00 eq) in MeOH (5.00 mL) was added Pd/C (80.0 mg)under N₂. The suspension was degassed under vacuum and purged withhydrogen several times. The mixture was stirred under hydrogen (15 psi)at 25° C. for 8 hours. The reaction mixture was filtered and thefiltrate was concentrated under reduced pressure to dryness to givetert-butyl4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(dimethylcarbamoyl)piperazine-1-carboxylate(197 mg, crude) as a brown solid, which was used directly in the nextstep without further purification. ESI MS m/z 620.3 [M+H]⁺.

Step D:4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-N,N-dimethyl-piperazine-2-carboxamide:A mixture of tert-butyl4-[2-[2-(dimethylamino)ethoxy]-7(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(dimethylcarbamoyl)piperazine-1-carboxylate(197 mg, crude) in DCM (5.00 mL) was added HCl/dioxane (4 M, 1.61 mL) at0° C. The reaction mixture was degassed and purged with nitrogen 3 timesand stirred at 25° C. for 2 hours under a nitrogen atmosphere. Thereaction mixture was concentrated under reduced pressure to dryness. Theresidue was purified by preparative HPLC (column: Phenomenex Synergi C18150*25*, 10μ; mobile phase: [water (0.05% HCl)-ACN]; B %: 10%-30%, 7.8min). The collected water phase was lyophilized to dryness to give4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-N,N-dimethyl-piperazine-2-carboxamide(90.0 mg, 171 μmol, 53.1% yield, 99.0% purity) as a brown solid. ESI MSm/z 520.2 [M+H]⁺.

Step E:4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-N,N-dimethyl-1-prop-2-enoyl-piperazine-2-carboxamide:To a solution of4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-N,N-dimethyl-piperazine-2-carboxamide(70.0 mg, 135 μmol, 1.00 eq) in DMAC (500 μL) was added triethylamine(40.9 mg, 404 μmol, 56.0 μL, 3.0 eq) at 0° C. and then prop-2-enoylprop-2-enoate (2.55 mg, 20.2 μmol, 0.15 eq) was added. The mixture wasstirred at 0° C. for 2 hours under a nitrogen atmosphere. The reactionmixture was filtered and the collected organic phase was purified bypreparative HPLC (column: Phenomenex Synergi C18 150*25*, 10μ; mobilephase: [water (0.1% TFA)-ACN]; B %: 15%-45%, 12 min). The collectedwater phase was lyophilized to give4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-N,N-dimethyl-1-prop-2-enoyl-piperazine-2-carboxamide(10.0 mg, 16.5 μmol, 12.2% yield, 94.6% purity) as a yellow semisolid.ESI MS m/z 574.2 [M+H]⁺.

Example 52

1-[4-[7-(3-hydroxy-1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: tert-butyl4-[7-benzyl-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of 2-(1-piperidyl)ethanol (872 mg, 6.75 mmol, 899 μL, 3.00eq) in toluene (40.0 mL) was added Pd(OAc)₂ (50.5 mg, 225 μmol, 0.10eq), Cs₂CO₃ (2.20 g, 6.75 mmol, 3.00 eq), BINAP (280 mg, 450 μmol, 0.20eq) and tert-butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(1.00 g, 2.25 mmol, 1.00 eq). The mixture was stirred at 110° C. for 12hours under N₂ and then concentrated under vacuum. The residue wasdiluted with water (10.0 mL), extracted with ethyl acetate (3×20 mL),washed with brine (1×50 mL), dried over Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by columnchromatography (SiO₂, DCM/MeOH=10:1) to give tert-butyl4-[7-benzyl-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(700 mg, 1.30 mmol, 58.0% yield) as a red solid. ESI MS m/z 537.3[M+H]⁺.

Step B: tert-butyl4-[2-[2-(1-piperidyl)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate: To a mixture of tert-butyl4-[7-benzyl-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(600 mg, 1.12 mmol, 1.00 eq) in MeOH (50.0 mL) was added Pd/C (67.2 mg,10%). The mixture was stirred at 40° C. for 24 hours at 50 psi under Hz.The mixture was filtered and concentrated under vacuum to givetert-butyl4-[2-[2-(1-piperidyl)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate (500 mg, crude) as a brown oil and used in thenext step without further purification. ESI MS m/z 447.3 [M+H]⁺.

Step C: tert-butyl4-[7-(3-methoxy-1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate: To a solution oftert-butyl4-[2-[2-(1-piperidyl)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(250 mg) and (3-methoxy-1-naphthyl) trifluoromethanesulfonate (343 mg,1.12 mmol) in toluene (6.00 mL) was added2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos) (52.3 mg,112 μmol), Pd₂(dba)₃ (32.19 mg, 55.98 μmol) and Cs₂CO₃ (548 mg, 1.68mmol). After stirring at 110° C. for 72 hours under N₂, the mixture wasconcentrated under vacuum, diluted with water (20.0 mL), extracted withethyl acetate (3×30.0 mL), washed with brine (1×50.0 mL), dried overNa₂SO₄, filtered and concentrated under vacuum. The residue was purifiedby column chromatography (SiO₂, DCM/MeOH=10:1) to give tert-butyl4-[7-(3-methoxy-1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate (140 mg, 232 μmol, twosteps, 41.5% yield) as a yellow solid. ESI MS m/z 603.3 [M+H]⁺.

Step D:7-(3-methoxy-1-naphthyl)-4-piperazin-1-yl-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine:A mixture of tert-butyl 4-[7-(3-methoxy-1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(120 mg, 199 μmol, 1.00 eq) and TFA (340 mg, 2.99 mmol, 221 μL, 15.0 eq)in DCM (1.00 mL) was stirred at 25° C. for 1 hour. The mixture wasconcentrated under vacuum to give7-(3-methoxy-1-naphthyl)-4-piperazin-1-yl-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidinebis-trifluoroacetate (145 mg, crude) as a yellow solid which was usedinto next step without further purification. ESI MS m/z 503.3 [M+H]⁺.

Step E: 1-[4-[7-(3-methoxy-1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a solution of7-(3-methoxy-1-naphthyl)-4-piperazin-1-yl-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidinebis-trifluoroacetate (145 mg, crude) and Et₃N (221 mg, 2.18 mmol, 303μL) in DCM (2.00 mL) was added prop-2-enoyl prop-2-enoate (25.0 mg, 198μmol) at −78° C. After stirring at 0° C. for 0.5 h, the mixture quenchedwith MeOH and concentrated under vacuum. The mixture was purified bycolumn chromatography (SiO₂, DCM/MeOH=10:1) to give1-[4-[7-(3-methoxy-1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(90.0 mg, 162 μmol, two steps 81.5% yield) a yellow solid. ESI MS m/z557.3 [M+H]⁺.

Step F:1-[4-[7-(3-hydroxy-1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a solution of 1-[4-[7-(3-methoxy-1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(90.0 mg, 162 μmol, 1.00 eq) in DCM (2.00 mL) was added BBr₃ (405 mg,1.62 mmol, 156 μL, 10.0 eq) at −78° C. After stirring at 0° C. for 1 h,the mixture was quenched with saturated sodium bicarbonate solution at−78° C. and stirred at 0° C. for 0.5 h. The mixture was extracted withethyl acetate (3×20.0 mL), washed with brine (1×40.0 mL), dried overNa₂SO₄, filtered and concentrated under vacuum. The residue was purifiedby preparative HPLC (Phenomenex Gemini 150*25 mm*, 10μ; mobile phase:[water (0.05% ammonia hydroxide v/v)-ACN]; B %: 55%-85%, 10 min) to give1-[4-[7-(3-hydroxy-1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(6.19 mg, 10.8 μmol, 6.71% yield, 95% purity) as a yellow oil. ESI MSm/z 543.2 [M+H]⁺.

Example 53

1-(4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-(hydroxymethyl)piperazin-1-yl)prop-2-en-1-one

Step A: 1-tert-butyl 3-methyl4-(7-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1,3-dicarboxylate:A mixture of 7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (3.00 g, 10.2 mmol, 1.00 eq), 1-tert-butyl-3-methylpiperazine-1,3-dicarboxylate (2.62 g, 10.7 mmol, 1.05 eq), DIEA (3.30 g,25.5 mmol, 4.45 mL, 2.50 eq) in DMSO (50.0 mL) was degassed and purgedwith nitrogen 3 times. The mixture was stirred at 100° C. for 12 hoursunder a nitrogen atmosphere. The reaction mixture was diluted with DCM(200 mL), washed with brine (3×50 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to dryness. The residue was purifiedby column chromatography (SiO₂, Petroleum ether/Ethyl acetate=10:1 to3:1) to give 1-tert-butyl 3-methyl4-(7-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1,3-dicarboxylate(2.10 g, 3.81 mmol, 37.4% yield, 91.0% purity) as a yellow oil. ESI MSm/z 502.1 [M+H]⁺.

Step B: 1-tert-butyl3-methyl4-(7-benzyl-2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-,3-dicarboxylateA mixture of 1-tert-butyl 3-methyl4-(7-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1,3-dicarboxylate(2.10 g, 4.17 mmol, 1.00 eq), 2-(dimethylamino)ethanol (929 mg, 10.4mmol, 1.04 mL, 2.50 eq), Pd(OAc)₂ (140 mg, 625 μmol, 0.15 eq), BINAP(519 mg, 833 μmol, 0.20 eq) and Cs₂CO₃ (3.39 g, 10.4 mmol, 2.50 eq) intoluene (60.0 mL) was degassed and purged with nitrogen for 3 times. Themixture was stirred at 110° C. for 3 hours under a nitrogen atmosphere.The reaction mixture was filtered and concentrated under reducedpressure to dryness. The residue was purified by column chromatography(SiO₂, DCM/MeOH=30:1 to 10:1) to give 1-tert-butyl3-methyl4(7-benzyl-2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1,3-dicarboxylate(1.30 g, 1.67 mmol, 40.0% yield, 71.4% purity) as a yellow solid. ESI MSm/z 555.3 [M+H]⁺.

Step C: 1-tert-butyl 3-methyl4-(2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1,3-dicarboxylate: To a solution of 1-tert-butyl 3-methyl4-(7-benzyl-2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1,3-dicarboxylate(1.30 g, 2.34 mmol, 1.00 eq) in MeOH (15.0 mL) was added Pd/C (300 mg)under N₂. The suspension was degassed under vacuum and purged withhydrogen several times. The mixture was stirred under hydrogen (50 psi)at 45° C. for 48 hours. The catalyst was filtered off and the filtratewas concentrated under reduced pressure to give 1-tert-butyl 3-methyl4-(2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1,3-dicarboxylate (780 mg, crude) as a colorless oil, whichwas used directly in the next step without further purification.

Step D: 1-tert-butyl 3-methyl4-(7-(3-(benzyloxy)naphthalen-1-yl)-2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1,3-dicarboxylate:A mixture of 1-tert-butyl 3-methyl4-(2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1,3-dicarboxylate(780 mg, crude), 3-benzyloxy-1-bromo-naphthalene (684 mg, 2.18 mmol),Pd₂(dba)₃ (231 mg, 252 μmol), Cs₂CO₃ (1.37 g, 4.20 mmol) and2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos) (157 mg, 336μmol) in dioxane (20.0 mL) was degassed and purged with nitrogen 3times. The mixture was stirred at 85° C. for 5 hours under a nitrogenatmosphere. The reaction mixture was filtered and concentrated underreduced pressure to dryness. The residue was purified by columnchromatography (SiO₂, DCM/MeOH=10:1 to 5:1) to give 1-tert-butyl3-methyl4-(7-(3-(benzyloxy)naphthalen-1-yl)-2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1,3-dicarboxylate(750 mg, 1.02 mmol, two steps 43.6% yield, 95.0% purity) as a yellowsolid. ¹H NMR (400 MHz, chloroform-d) δ=8.10 (d, J=8.0 Hz, 1H), 7.73 (d,J=8.0 Hz, 1H), 7.58-7.31 (m, 8H), 7.00 (d, J=2.0 Hz, 1H), 6.89 (d, J=2.0Hz, 1H), 5.18 (s, 2H), 4.75 (br s, 1H), 4.45 (br d, J=13.2 Hz, 1H),4.42-4.34 (m, 1H), 4.34-4.28 (m, 1H), 4.15 (br s., 2H), 4.13-3.91 (m,1H), 3.85-3.70 (m, 5H), 3.49-3.33 (m, 2H), 3.31-3.07 (m, 2H), 2.99 (brs, 1H), 2.83-2.68 (m, 3H), 2.35 (s, 6H), 1.48 (s, 9H).

Step E: methyl1-(7-(3-(benzyloxy)naphthalen-1-yl)-2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-2-carboxylate:To a solution of 1-tert-butyl 3-methyl4-(7-(3-(benzyloxy)naphthalen-1-yl)-2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1,3-dicarboxylate(200 mg, 287 μmol, 1.00 eq) in DCM (5.00 mL) was added TFA (770 mg, 6.75mmol, 500 μL, 23.5 eq) at 0° C. The mixture was stirred at 25° C. for 2hours under a nitrogen atmosphere. The reaction mixture was concentratedunder reduced pressure to dryness. The residue was dissolved in DCM (100mL) and water (50 mL) and the solution was adjusted to pH 8 withsaturated Na₂CO₃ aqueous and then extracted with DCM (3×50 mL). Thecombined organic layers were washed with brine (3×50 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give methyl1-(7-(3-(benzyloxy)naphthalen-1-yl)-2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-2-carboxylate(171 mg, 263 μmol, 91.6% yield, 91.7% purity) as a yellow solid. ESI MSm/z 597.2 [M+H]⁺.

Step F: (1-(7-(3-(benzyloxy)naphthalen-1-yl)-2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)methanol:To a mixture of methyl1-(7-(3-(benzyloxy)naphthalen-1-yl)-2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-2-carboxylate(171 mg, 287 μmol, 1.00 eq) in THF (5.00 mL) was added LiAlH₄ (65.3 mg,1.72 mmol, 6.00 eq) at 0° C. After stirring for 2 hours at 25° C., thereaction mixture was quenched by addition of water (30 mL) at 0° C., andextracted with DCM (3×30 mL). The combined organic layers were washedwith brine (3×30 mL). The collected organic phase was dried over Na₂SO₄,filtered and concentrated under reduced pressure to give(1-(7-(3-(benzyloxy)naphthalen-1-yl)-2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)methanol(160 mg, 281 μmol, 98.2% yield, 100% purity) as a colorless semisolid.ESI MS m/z 569.2 [M+H]⁺.

Step G:2-((7-(3-(benzyloxy)naphthalen-1-yl)-4-(2-(((tert-butyldimethylsilyl)oxy)methyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)-N,N-dimethylethanamine:To a mixture of(1-(7-(3-(benzyloxy)naphthalen-1-yl)-2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)methanol(160 mg, 281 μmol, 1.00 eq) in THF (5.00 mL) was added NaH (94.0 mg,2.35 mmol, 60.0% purity, 8.00 eq) at 0° C. After stirring for 30minutes, tert-butyldimethylsilyl chloride (133 mg, 881 μmol, 108 μL,3.00 eq) was added dropwise. The mixture was stirred at 25° C. for 6hours under a nitrogen atmosphere. The reaction mixture was concentratedunder reduced pressure to give2-((7-(3-(benzyloxy)naphthalen-1-yl)-4-(2-(((tert-butyldimethylsilyl)oxy)methyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)-N,N-dimethylethanamine(133 mg, 165 μmol, 56.1% yield, 84.6% purity) as a slight yellow solid,which was used directly in the next step without further purification.ESI MS m/z 683.2 [M+H]⁺.

Step H: 1-(4-(7-(3-(benzyloxy)naphthalene-1-yl)-2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)piperazin-1-yl)prop-2-en-1-one:1 To a solution of2-((7-(3-(benzyloxy)naphthalen-1-yl)-4-(2-(((tert-butyldimethylsilyl)oxy)methyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)-N,N-dimethylethanamine(133 mg, 165 μmol, 1.00 eq) and TEA (39.4 mg, 389 μmol, 54.0 μL, 2.00eq) in DCM (3.00 mL) was added prop-2-enoyl prop-2-enoate (31.9 mg, 253μmol, 1.30 eq) at −40° C. After stirring at −40° C. for 2 hours, thereaction mixture was quenched with MeOH (1 M) and concentrated underreduced pressure to give 1-(4-(7-(3-(benzyloxy)naphthalene-1-yl)-2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)piperazin-1-yl)prop-2-en-1-one(140 mg, crude) as a yellow solid. ESI MS m/z 737.2 [M+H]⁺.

Step I:1-(4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-(hydroxymethyl)piperazin-1-yl)prop-2-en-1-one:To a solution of1-(4-(7-(3-(benzyloxy)naphthalen-1-yl)-2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)piperazin-1-yl)prop-2-en-1-one(140 mg, crude) in DCM (5.00 mL) was added BBr₃ (476 mg, 1.90 mmol, 183μL) at −40° C. After stirring for 2 hours at −40° C. under a nitrogenatmosphere, the mixture was concentrated under reduced pressure todryness. Water (0.5 mL) and MeOH (2.5 mL) were added and the resultingsolution was purified by preparative HPLC (column: Waters Xbridge 150*255 u; mobile phase. [water (10 mM NH₄HCO₃)-ACN]; B %: 27%-57%, 11 min).The desired fractions were collected and lyophilized to give1-(4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-(hydroxymethyl)piperazin-1-yl)prop-2-en-1-one(4.32 mg, 7.94 μmol, 4.18% yield, 97.9% purity) as a white solid. ESI MSm/z 533.4 [M+H]⁺.

Example 54

1-[4-[7-(3-amino-1-isoquinolyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: tert-butyl 4-hydroxy-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate: To a solution of Na (4.24 g, 184 mmol,4.37 mL, 2.50 eq) in EtOH (400 mL) was added 1-tert-butyl 4-ethyl3-oxopiperidine-1,4-dicarboxylate (20.0 g, 73.7 mmol, 1.00 eq) andacetic acid methanimidamide (11.5 g, 111 mmol, 1.50 eq) under N₂. Themixture was stirred at 70° C. for 5 hours. The reaction mixture wasadjusted to pH 7 with HCl (1N), extracted with DCM (3×200 mL), washedwith brine (1×400 mL), dried over Na₂SO₄, filtered and concentratedunder vacuum to give tert-butyl 4-hydroxy-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (16.0 g, 63.7 mmol, 86.4% yield) as abrown solid. ESI MS m/z 274.0 [M+H]⁺.

Step B: tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate:To a solution of tert-butyl 4-hydroxy-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (16.0 g, 63.7 mmol, 1.00 eq) in DMF (4.00 mL)was added DBU (29.1 g, 191 mmol, 28.8 mL, 3.00 eq) andbenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(PYBOP) (39.8 g, 76.4 mmol, 1.20 eq). The mixture was stirred at 25° C.for 1 hour. Benzyl piperazine-1-carboxylate (21.0 g, 95.5 mmol, 18.5 mL,1.50 eq) was added and the reaction mixture was stirred at 25° C. for 16hours. The mixture was diluted with ethyl acetate (500 mL) and washedwith water (3×400 mL), dried over Na₂SO₄, filtered and concentratedunder vacuum. The residue was purified by column chromatography (SiO₂,diethyl ether/ethyl acetate=1:1) to give tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(2.00 g, 4.41 mmol, 6.93% yield) as a yellow oil. ESI MS m/z 454.3[M+H]⁺.

Step C: A mixture of tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(1.20 g, 2.65 mmol, 1.00 eq) and TFA (4.53 g, 39.7 mmol, 2.94 mL, 15.0eq) in DCM (2.00 mL) was stirred at 25° C. for 1 hour. The mixture wasconcentrated under vacuum. The concentrated material was adjusted to pH8 with saturated aq. NaHCO₃, then extracted with ethyl acetate (3×30.0mL), washed with brine (1×100 mL), dried over Na₂SO₄, filtered andconcentrated under vacuum to give benzyl4-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (800 mg, 2.26 mmol, 85.4% yield)as a yellow oil. ESI MS m/z 354.3 [M+H]⁺.

Step D: benzyl4-[7-[3-(tert-butoxycarbonylamino)-1-isoquinolyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:A mixture of tert-butyl N-(1-bromo-3-isoquinolyl)carbamate (330 mg, 1.02mmol, 1.00 eq), DIEA (264 mg, 2.04 mmol, 357 μL, 2.00 eq) and benzyl4-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(541 mg, 1.53 mmol, 1.50 eq) in DMSO (3.00 mL) was stirred at 80° C. for10 hours. The mixture was diluted with water (5.00 mL) and extractedwith ethyl acetate (3×20 mL). The combined extracts were dried oversodium sulfate, filtered and concentrated under vacuum. The residue waspurified by reverse-phase column (TFA, 0.1%) to give benzyl4-[7-[3-(tert-butoxycarbonylamino)-1-isoquinolyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(400 mg, 665 μmol, 65.2% yield) as a yellow solid. ESI MS m/z 596.3[M+H]⁺.

Step E: tert-butylN-[1-(4-piperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl)-3-isoquinolyl]carbamate:A mixture of benzyl4-[7-[3-(tert-butoxycarbonylamino)-1-isoquinolyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(240 mg, 403 μmol, 1.00 eq), KOH (36.2 mg, 645 μmol, 1.60 eq) in H₂O(2.40 mL) and n-butyl alcohol (2.40 mL) was stirred at 100° C. for 12hours. The mixture was diluted with ethyl acetate (3×5.00 mL), washedwith brine (1×10.0 mL), dried over Na₂SO₄, filtered and concentratedunder vacuum to give tert-butylN-[1-(4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl)-3-isoquinolyl]carbamate(150 mg, 325 μmol, 80.7% yield) as a yellow oil. ESI MS m/z 462.3[M+H]⁺.

Step F:1-(4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl)isoquinolin-3-aminetrifluoroacetate: A solution of tert-butylN-[1-(4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl)-3-isoquinolyl]carbamate(150 mg, 325 μmol, 1.00 eq) and TFA (556 mg, 4.87 mmol, 361 μL, 15.0 eq)in DCM (360 μL) was stirred at 25° C. for 1 hours. The mixture wasconcentrated under vacuum to give1-(4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl)isoquinolin-3-aminetrifluoroacetate (154.52 mg, crude) as a yellow solid which was usedinto next step without further purification.

Step G:1-[4-[7-(3-amino-1-isoquinolyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a solution of 1-(4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl)isoquinolin-3-amine trifluoroacetate (150 mg, crude) andEt₃N (319 mg, 3.15 mmol, 437 μL) in DCM (2.00 mL) was added prop-2-enoylprop-2-enoate (31.8 mg, 252 μmol) at −40° C., then stirred at −40° C.for 0.5 h. The mixture was quenched by adding MeOH (20.22 mg, 630.96μmol) and concentrated under vacuum. The residue was purified bypreparative HPLC (Phenomenex Gemini 150*25 mm*, 10μ; mobile phase:[water (0.05% ammonia hydroxide v/v)-ACN]; B %: 26%-56%, 10 min) to give1-[4-[7-(3-amino-1-isoquinolyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(35.4 mg, 82.5 μmol, 26.2% yield, 96.8% purity) as a yellow solid. ESIMS m/z 416.3 [M+H]⁺.

Example 55

1-(4-(2-(2-(dimethylamino)-3-hydroxypropoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-(dimethylamino)propane-1,3-diol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 533.3 [M+H]⁺.

Example 56

(R)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-morpholinopropan-2-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(R)-1-morpholinopropan-2-ol in place of (S)-1-(dimethylamino)propan-2-olin Step B. ES+APCI MS m/z 559.3 [M+H]⁺.

Example 57

(S)-5-(((4-(4-acryloylpiperazin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)pyrrolidin-2-one

Synthesized according to the method of Example 8, using(S)-5-(hydroxymethyl)pyrrolidin-2-one in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 529.3 [M+H]⁺.

Example 58

(R)-5-(((4-(4-acryloylpiperazin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)pyrrolidin-2-one

Synthesized according to the method of Example 8, using(R)-5-(hydroxymethyl)pyrrolidin-2-one in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 529.2 [M+H]⁺.

Example 59

N-(2-((4-(4-acryloylpiperazin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)ethyl)acetamide

Synthesized according to the method of Example 8, usingN-(2-hydroxyethyl)acetamide in place of (S)-1-(dimethylamino)propan-2-olin Step B. ES+APCI MS m/z 517.3 [M+H]⁺.

Example 60

(R)-1-(4-(2-((1-(dimethylamino)butan-2-yl)oxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(R)-1-(dimethylamino)butan-2-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 545.3 [M+H]⁺.

Example 61

(S)-6-(((4-(4-acryloylpiperazin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)piperidin-2-one

Synthesized according to the method of Example 8, using6-(hydroxymethyl)piperidin-2-one in place of(S)-1-(dimethylamino)propan-2-ol in Step B and the product was separatedby chiral chromatography Peak 2 was given the (S) stereochemistry andthis was not confirmed ES+APCI MS m/z 543.3 [M+H]⁺.

Example 62

(R)-6-(((4-(4-acryloylpiperazin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)piperidin-2-one

Synthesized according to the method of Example 8, using6-(hydroxymethyl)piperidin-2-one in place of(S)-1-(dimethylamino)propan-2-ol in Step B and separated by chiralchromatography. Peak 1 was assigned the (R) stereochemistry but thisstereochemistry was not confirmed. ES+APCI MS m/z 543.2 [M+H]⁺.

Example 63

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(((R)-1-((R)-3-methoxypyrrolidin-1-ylpropan-2-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(R)-1-((R)-3-methoxypyrrolidin-1-ylpropan-2-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 573.3 [M+H]⁺.

Example 64

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(((R)-1-((S)-3-methoxypyrrolidin-1-ylpropan-2-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(R)-1-((S)-3-methoxypyrrolidin-1-ylpropan-2-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 573.3 [M+H]⁺.

Example 65

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(((R)-1-((S)-3-hydroxypyrrolidin-1-ylpropan-2-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(R)-1-((S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-ylpropan-2-ol inplace of (S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z559.3 [M+H]⁺.

Example 66

(S)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpiperidin-3-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(S)-1-methylpiperidin-3-ol in place of (S)-1-(dimethylamino)propan-2-olin Step B. ES+APCI MS nm/z 529.3 [M+H]⁺.

Example 67

(R)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpiperidin-3-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(R)-1-methylpiperidin-3-ol in place of (S)-1-(dimethylamino)propan-2-olin Step B. ES+APCI MS m/z 529.3 [M+H]⁺.

Example 68

(R)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using1-iodonaphthalene in place of (3-(methoxymethoxy)naphthalen-1yltrifluoromethanesulfonate in Step D. ES+APCI MS m/z 501.3 [M+H]⁺.

Example 69

1-(4-(7-(isoquinolin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 1, using4-bromoisoquinoline in place of 1-bromo-3-(methoxymethoxy)naphthalene inStep C. ES+APCI MS m/z 401.2 [M+H]⁺.

Example 70

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-(methylamino)propan-2-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using1-(methylamino)propan-2-ol in place of (S)-1-(dimethylamino)propan-2-olin Step B. ES+APCI MS m/z 503.3 [M+H]⁺.

Example 71

1-(4-(7-(2-hydroxy-1-phenylethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 1, using2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl methanesulfonate in placeof 1-bromo-3-(methoxymethoxy)naphthalene in Step C. ES+APCI MS m/z 394.2[M+H]⁺.

Example 72

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpiperidin-3-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(1-methylpiperidin-3-yl)methanol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 543.3 [M+H]⁺.

1-(4-(2-(2-(dimethylamino)propoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-(dimethylamino)propan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 517.2 [M+H]⁺.

Example 74

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using3-morpholinopropan-1-ol in place of (S)-1-(dimethylamino)propan-2-ol inStep B. ES+APCI MS m/z 559.3 [M+H]⁺.

Example 75

(R)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-(piperidin-1-yl)propan-2-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(R)-1-(piperidin-1-yl)propan-2-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 557.3 [M+H]⁺.

Example 76

(R)-1-(4-(7-(3-chloro-5-hydroxy-2-isopropylphenyl)-2-((1-(dimethylamino)propan-2-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using1-bromo-3-chloro-2-isopropyl-5-(methoxymethoxy)benzene in place of(3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate in Step D.ES+APCI MS m/z 545.3 [M+H]⁺.

Example 77

1-(4-(2-(2-((1S,4R)-2-azabicyclo[2.2.1]heptan-2-yl)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-((1S,4R)-2-azabicyclo[2.2.1]heptan-2-yl)ethan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 555.2 [M+H]⁺.

Example 78

(R)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(5-hydroxy-2-(trifluoromethoxy)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-bromo-4-(methoxymethoxy)-1-(trifluoromethoxy)benzene in place of(3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate in Step D.ES+APCI MS m/z 551.2 [M+H]⁺.

Example 79

(R)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(5-hydroxy-2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-bromo-4-(methoxymethoxy)-1-(trifluoromethyl)benzene in place of(3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate in Step D.ES+APCI MS m/z 535.2 [M+H]⁺.

Example 80

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((4-methylpiperazin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(4-methylpiperazin-2-yl)methanol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 544.3 [M+H]⁺.

Example 81

1-(2-((4-(4-acryloylpiperazin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)ethyl)piperidine-4-carbonitrile

Synthesized according to the method of Example 8, using1-(2-hydroxyethyl)piperidine-4-carbonitrile in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 568.2 [M+H]⁺.

Example 82

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(3-(4-methylpiperazin-1-yl)propoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8,3-(4-methylpiperazin-1-yl)propan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 572.4 [M+H]⁺.

Example 83

1-(4-(2-(2-((2-hydroxyethyl)(methyl)amino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-((2-((tert-butyldimethylsilyl)oxy)ethyl)(methyl)amino)ethan-1-ol inplace of (S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z533.3 [M+H]⁺.

Example 84

(R)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(2-fluoro-6-hydroxy-3-methylphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-bromo-3-fluoro-1-(methoxymethoxy)-4-methylbenzene in place of(3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate in Step D.ES+APCI MS m/z 499.3 [M+H]⁺.

Example 85

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-(pyrrolidin-1-yl)ethan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 529.2 [M+H]⁺.

Example 86

(R)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(2-hydroxy-5-(trifluoromethoxy)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-bromo-1-(methoxymethoxy)-4-(trifluoromethoxy)benzene in place of(3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate in Step D.ES+APCI MS m/z 551.2 [M+H]⁺.

Example 87

(R)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-fluoro-2-hydroxy-6-methylphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-bromo-4-fluoro-3-(methoxymethoxy)-1-methylbenzene in place of(3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate in Step D.ES+APCI MS m/z 499.2 [M+H]⁺.

Example 88

(S)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(2-(2-methylpiperidin-1-yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(S)-2-(2-methylpiperidin-1-yl)ethan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 557.2 [M+H]⁺.

Example 89

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpyrrolidin-3-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(I-methylpyrrolidin-3-yl)methanol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 529.3 [M+H]⁺.

Example 90

1-(4-(7-(5-hydroxy-2-(trifluoromethoxy)phenyl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using3-morpholinopropan-1-ol in place of (S)-1-(dimethylamino)propan-2-ol inStep B, and using 2-bromo-4-(methoxymethoxy)-1-(trifluoromethoxy)benzenein place of (3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonatein Step D. ES+APCI MS m/z 593.2 [M+H]⁺.

Example 91

(R)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-hydroxy-5-(trifluoromethoxy)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using3-bromo-1-(methoxymethoxy)-5-(trifluoromethoxy)benzene in place of(3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate in Step D.ES+APCI MS m/z 551.2 [M+H]⁺.

Example 92

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(2-(4-methylpiperidin-1-yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-(4-methylpiperidin-1-yl)ethan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 557.2 [M+H]⁺.

Example 93

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((4-morpholinobutan-2-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using4-morpholinobutan-2-ol in place of (S)-1-(dimethylamino)propan-2-ol inStep B. ES+APCI MS m/z 573.3 [M+H]⁺.

Example 94

(R)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(5-hydroxy-2-methoxyphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using3-bromo-1-(methoxymethoxy)-4-methoxybenzene in place of(3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate in Step D.ES+APCI MS m/z 497.2 [M+H]⁺.

Example 95

(R)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(2-hydroxy-6-methylphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-bromo-1-(methoxymethoxy)-3-methylbenzene in place of(3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate in Step D.ES+APCI MS m/z 481.2 [M+H]⁺.

Example 96

1-(4-(7-(5-hydroxy-2-isopropoxyphenyl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using3-morpholinopropan-1-ol in place of (S)-1-(dimethylamino)propan-2-ol inStep B, and using 2-bromo-4-(methoxymethoxy)-1-(isopropoxy)benzene inplace of (3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate inStep D. ES+APCI MS m/z 567.2 [M+H]⁺.

Example 97

(R)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(2-(2-methylpiperidin-1-yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(R)-2-(2-methylpiperidin-1-yl)ethan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 557.3

Example 98

(S)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(2-(3-methoxypiperidin-1-yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(S)-2-(3-methoxypiperidin-1-yl)ethan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 557.3 [M+H]⁺.

Example 99

(R)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(2-(3-methoxypiperidin-1-yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(R)-2-(3-methoxypiperidin-1-yl)ethan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 557.3 [M+H]⁺.

Example 100

1-(4-(2-((1-cyclopropylpiperidin-4-yl)oxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(1-cyclopropylpiperidin-4-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 555.3 [M+H]⁺.

Example 101

1-(4-(2-(3-(1,4-oxazepan-4-yl)propoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(3-(1,4-oxazepan-4-yl)propan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 573.3 [M+H]⁺.

Example 102

1-(4-(2-(3-(1,4-oxazepan-4-yl)propoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-(diethylamino)ethan-1-ol in place of (S)-1-(dimethylamino)propan-2-olin Step B. ES+APCI MS m/z 531.3 [M+H]⁺.

Example 103

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-(2-methoxyethyl)pyrolidin-3-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8,(1-(2-methoxyethyl)pyrrolidin-3-yl)methanol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 573.3 [M+H]⁺.

Example 104

1-(4-(2-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 571.3 [M+H]⁺.

Example 105

1-(4-(7-(5-hydroxy-2-methylphenyl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using3-morpholinopropan-1-ol in place of (S)-1-(dimethylamino)propan-2-ol inStep B, and using 2-bromo-4-(methoxymethoxy)-1-methylbenzene in place of(3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate in Step D.ES+APCI MS m/z 523.3 [M+H]⁺.

Example 106

1-(4-(7-(4-hydroxy-2-(trifluoromethoxy)phenyl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using3-morpholinopropan-1-ol in place of (S)-1-(dimethylamino)propan-2-ol inStep B, and using 2-bromo-5-(methoxymethoxy)-1-(trifluoromethoxy)benzenein place of (3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonatein Step D. ES+APCI MS m/z 593.2 [M+H]⁺.

Example 107

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(2-((2-methoxyethyl)(methyl)amino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-((2-methoxyethyl)(methyl)amino)ethan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 547.3 [M+H]⁺.

Example 108

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(2-(4-methoxypiperidin-1-yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-(4-methoxypiperidin-1-yl)ethan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 573.3 [M+H]⁺.

Example 109

1-(4-(2-(2-(4,4-difluoropiperidin-1-yl)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-(4,4-difluoropiperidin-1-yl)ethan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 579.2 [M+H]⁺.

Example 110

(R)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpyrrolidin-3-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(R)-(1-methylpyrrolidin-3-yl)methanol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 529.3 [M+H]⁺.

Example 111

(S)-1-(4-(2-(2-(3-fluoropiperidin-1-yl)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(S)-2-(3-fluoropiperidin-1-yl)ethan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 561.3 [M+H]⁺.

Example 112

1-(4-(7-(3-(difluoromethyl)naphthalen-1-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using3-morpholinopropan-1-ol in place of (S)-1-(dimethylamino)propan-2-ol inStep B, and using 1-bromo-3-(difluoromethyl)naphthalene (0.129 g, 0.503mmol) in place of (3-(methoxymethoxy)naphthalen-1-yltrifluoromethanesulfonate in Step D. ES-+APCI MS m/z 593.2 [M+H]⁺.

Example 113

4-(4-acryloylpiperazin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-7,8-dihydropyrido[3,4-d]pyrimidin-6(5H)-one

Step A: tert-butyl4-(6-fluoropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate: To asolution of 4-chloro-6-fluoropyrido[3,4-d]pyrimidine (1.07 g, 5.83 mmol)in DCM (20 mL) was added N-ethyl-N-isopropylpropan-2-amine (2.09 mL,11.7 mmol) followed by tert-butyl piperazine-1-carboxylate (1.19 g, 6.41mmol) and the reaction stirred at room temperature for 2 hours. Thereaction mixture was washed with brine, dried over MgSO₄ andconcentrated in vacuo to provide tert-butyl4-(6-fluoropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate, whichwas used directly in the next step (1.8 g, 92.6%). ES+APCI MS m/z 334.1[M+H]⁺.

Step B: tert-butyl4-(6-(benzyloxy)pyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate: Toa solution of phenylmethanol (0.65 g, 6.0 mmol) in DMA (10 mL) was addedsodium hydride (0.24 g, 6.0 mmol) in portions while degassing withnitrogen and the reaction mixture was stirred for 30 minutes at roomtemperature. To the reaction was added tert-butyl4-(6-fluoropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (1.0 g,3.0 mmol) as a solid and the reaction mixture was stirred at roomtemperature for 3 hours. The reaction was poured into water (300 mL) andthe aqueous layer extracted with ethyl acetate. The organic layer waswashed with brine, dried over MgSO₄ and concentrated in vacuo. The crudematerial was chromatographed using a gradient of 0 to 100% ethylacetate/DCM as the eluent to give tert-butyl4-(6-(benzyloxy)pyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.4 g, 0.95 mmol, 32% yield). ES+APCI MS m/z 422.2 [M+H]⁺.

Step C: tert-butyl4(6-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:To a solution of tert-butyl4-(6-(benzyloxy)pyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.40 g, 0.95 mmol) in 95% ethanol (30 mL) purged with nitrogen wasadded Pd/C (0.10 g, 0.95 mmol). The reaction was evacuated with vacuumand backfilled with hydrogen three times. After the third backfill thereaction mixture was stirred at room temperature for 4 hours. Thereaction was again degassed with nitrogen, the slurry filtered throughCelite® and the filtrate was concentrated in vacuo to give tert-butyl4-(6-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.4 g, 126%). ES+APCI MS m/z 334.4 [M+H]⁺.

Step D: tert-butyl4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-6-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:To a solution of tert-butyl4-(6-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.28 g, 0.84 mmol) in dioxanes (4 mL) in a sealed tube was addedpotassium phosphate (0.36 g, 1.7 mmol), N₁,N₂-dimethylethane-1,2-diamine(0.074 g, 0.84 mmol) and 1-iodo-3-(methoxymethoxy)naphthalene (0.53 g,1.7 mmol). The reaction sparged with argon for 20 minutes, followed byaddition of copper(I) iodide (0.16 g, 0.84 mmol). The reaction vesselsealed and heated to 100° C. overnight. The reaction was diluted withwater and the aqueous layer extracted with ethyl acetate (2×150 mL). Theorganics were washed with brine, dried over MgSO₄ and concentrated invacuo. The material was chromatographed using a gradient of 0 to 100%ethyl acetate/DCM as the eluent to give tert-butyl4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-6-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.30 g, 0.58 mmol, 69% yield) ES+APCI MS m/z 520.2 [M+H]⁺.

Step E:7-(3-hydroxynaphthalen-1-yl)-4-(piperazin-1-yl)-7,8-dihydropyrido[3,4-d]pyrimidin-6(5H)-one:To a solution of tert-butyl4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-6-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.30 g, 0.58 mmol) in methanol (10 mL) was added aqueous hydrogenchloride (0.38 mL, 2.3 mmol) and the reaction stirred over night at 50°C. The reaction was concentrated in vacuo to give7-(3-hydroxynaphthalen-1-yl)-4-(piperazin-1-yl)-7,8-dihydropyrido[3,4-d]pyrimidin-6(5H)-oneas the bis HCl salt (0.26 g, 100%). ES+APCI MS m/z 376.1 [M+H]⁺.

Step F:4-(4-acryloylpiperazin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-7,8-dihydropyrido[3,4-d]pyrimidin-6(5H)-one:To a slurry of7-(3-hydroxynaphthalen-1-yl)-4-(piperazin-1-yl)-7,8-dihydropyrido[3,4-d]pyrimidin-6(5H)-onedihydrochloride (0.26 g, 0.58 mmol) in a 1:1 solution ofDCM/acetonitrile (10 mL) was added N-ethyl-N-isopropylpropan-2-amine(0.45 g, 3.5 mmol) and acryloyl chloride (0.052 g, 0.58 mmol) and thereaction stirred at room temperature for 1 hour. The reaction wasconcentrated in vacuo and the material purified by reverse preparativeHPLC (using a gradient of 5 to 95% ACN/water) to give4-(4-acryloylpiperazin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-7,8-dihydropyrido[3,4-d]pyrimidin-6(5H)-one(0.038 g, 0.088 mmol, 15% yield). ES+APCI MS m/z 430.2 [M+H]⁺.

Example 114

4-(6-acryloyl-2,6-diazaspiro[3.3]heptan-2-yl)-7-(3-hydroxynaphthalen-1-yl)-7,8-dihydropyrido[3,4-d]pyrimidin-6(5H)-one

Synthesized according to the method of Example 8, using tert-butyl2,6-diazaspiro[3.3]heptane-2-carboxylate hydrochloride (305 mg, 1.54mmol) in place of tert-butyl piperazine-1-carboxylate (1.19 g, 6.41mmol) in Step B. ES+APCI MS m/z 442.2 [M+H]⁺

Example 115

1-((S)-4-(2-(((R)-1-(dimethylamino)propan-2-yl)oxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using benzyl(S)-3-methylpiperazine-1-carboxylate (1.155 g, 4.931 mmol) in place ofBenzyl 1-piperazinecarboxylate in step A. ES+APCI MS m/z 531.3 [M+H]⁺.

Example 116

(S)-1-(4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using benzyl(S)-3-methylpiperazine-1-carboxylate (1.155 g, 4.931 mmol) in place ofBenzyl 1-piperazinecarboxylate in step A. Also, using2-(dimethylamino)ethan-1-ol in place of (S)-1-(dimethylamino)propan-2-olin Step B. ES+APCI MS m/z 517.3 [M+H]⁺.

Example 117

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(2-morpholinoethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-morpholinoethan-1-ol in place of (S)-1-(dimethylamino)propan-2-ol inStep B. ES+APCI MS m/z 545.2 [M+H]⁺.

Example 118

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using morpholine inplace of (S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z501.3 [M+H]⁺.

Example 119

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(pyrrolidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using pyrrolidine inplace of (S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z485.2 [M+H]⁺.

Example 120

(R)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylpropan-2-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(R)-1-(pyrrolidin-1-yl)propan-2-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 543.4 [M+H]⁺.

Example 121

4-(4-acryloylpiperazin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-2-(3-morpholinopropoxy)-6,7-dihydropyrido[3,4-d]pyrimidin-8(5H)-one

Step A: Tert-butyl2,4-dichloro-8-oxo-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate.To a round bottom flask was added tert-Butyl2,4-dichloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (1.0g, 3.29 mmol) and EtOAc (16.4 mL). A solution of sodium periodate (2.11g, 9.86 mmol) in water (16.4 mL) was added. Ruthenium (III) chloride(0.102 g, 0.493 mmol) was added and the mixture was stirred looselycapped and vigorously stirred for 6 h at ambient temperature. Themixture was partitioned between water and EtOAc and the layers wereseparated. The aqueous layer was extracted further with EtOAc (2×20 mL)and the combined extracts were washed with brine and dried over Na₂SO₄,filtered and concentrated. The crude product was purified via columnchromatography (10-30% EtOAc/hexanes, loading with CH₂Cl₂) to afford0.864 g (82%) of the product as an off-white solid.

Step B: Tert-butyl4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-chloro-8-oxo-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate.To a solution of tert-butyl2,4-dichloro-8-oxo-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(0.400 g, 1.26 mmol) in CH₂Cl₂ (5.0 mL) was addedN,N-Diisopropylethylamine (0.325 g, 2.51 mmol) followed by benzyl1-piperazinecarboxylate (0.255 mL, 1.32 mmol) and the reaction stirredat ambient temperature for 1.5 h. The reaction mixture was diluted withCH₂Cl₃ (10 mL) and washed with a 0.5M KHSO₄ solution (5 mL), followed bya saturated aqueous NaHCO₃ solution and brine. The organic layer wasdried over Na₂SO₄, filtered and concentrated. The crude product wassonicated in 10 mL MTBE and the resulting solid was isolated by vacuumfiltration. The solid was dried in vacuo to provide 0.507 g (80%) of thedesired product as an off-white solid which was used directly in thenext step. ES+APCI MS m/z 502.1 [M+H]⁺.

Step C: Benzyl4-(2-chloro-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate.A solution of tert-butyl4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-chloro-8-oxo-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(0.255 g, 0.5080 mmol) in CH₂Cl₂ (1.0 mL) was cooled to 0° C.Trifluoroacetic acid (0.3890 mL, 5.080 mmol) was added and the mixturewas warmed to ambient temperature. After 1 hour the mixture was dilutedwith CH₂Cl₂ and added to a mixture brine (10 mL) and 3.0 M aqueous NaOH(1.7 ml, 5.080 mmol). The layers were combined and adjusted to pH 8 withsaturated aqueous NaHCO₃ solution. The layers were separated and theaqueous phase was extracted with 2×10 mL of CH₂Cl₂. The combined organiclayers were dried over Na₂SO₄, filtered and concentrated under vacuum.The title compound (0.223 g, quant.) was obtained as a yellow/orangefoam. ES+APCI MS m/z 402.1 [M+H]⁺.

Step D: Benzyl4-(2-(3-morpholinopropoxy)-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate.To a vial was added N-Hydroxypropanylmorpholine (0.687 g, 4.73 mmol) andbenzyl4-(2-chloro-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.190 g, 0.473 mmol) followed by dioxane (1.6 mL). Cesium carbonate(0.462 g, 1.42 mmol) was added and the mixture was stirred at 65° C. for15 hours. The mixture was diluted with CHCl₃ and filtered, and the solidwas washed with additional CHCl₃. The filtrate was concentrated in vacuoand was purified by column chromatography (2-10% MeOH/DCM with 1% NH₄OH)to afford 0.061 g (25%) of the desired product as a thick, colorlessoil. ES+APCI MS m/z 511.2[M+H]⁺.

Step E: Benzyl4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(3-morpholinopropoxy)-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate.To a vial was added benzyl4-(2-(3-morpholinopropoxy)-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.060 g, 0.12 mmol), N,N′-Dimethylethylenediamine (0.010 g, 0.12 mmol)and 1-iodo-3-(methoxymethoxy)naphthalene (0.074 g, 0.24 mmol) followedby dioxane (0.78 mL) and Potassium phosphate tribasic (0.050 g, 0.24mmol). The reaction was purged with bubbling Ar for 10 min, then Copper(I) Iodide (0.022 g, 0.12 mmol) was added and the vial was sealed. Themixture was heated to 110° C. and stirred for 16 hours. The mixture wascooled to ambient temperature, diluted with water and extracted withEtOAc (3×10 mL). The combined organic extracts were dried over Na₂SO₄,filtered and concentrated. The mixture was purified via columnchromatography (2-8% MeOH/DCM) to afford 0.062 g (76%) of the product asa tan foam. ES+APCI MS m/z 697.3 [M+H]⁺.

Step F:7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(3-morpholinopropoxy)-4-(piperazin-1-yl)-6,7-dihydropyrido[3,4-d]pyrimidin-8(5H)-one.To a solution of benzyl4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(3-morpholinopropoxy)-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.062 g, 0.089 mmol) in EtOH (0.44 mL) and THF (0.44 mL) was addedPalladium on Carbon (0.038 g, 0.018 mmol) (Degussa Type, 10 wt %, 50%H₂O) and then an atmosphere of hydrogen was introduced via vacuumfollowed by balloon pressure. The mixture was stirred at ambienttemperature for 1.5 h, then warmed to 45° C. and stirred for 1 hour. Themixture was diluted with EtOAc and filtered through a nylon filter. Thefiltrate was concentrated in vacuo providing a light tan foam (0.052 g)that was dried overnight and resubmitted to the same reaction conditionsabove. After stirring at ambient temperature for 5 h additional Pd/C(0.050 g) was added and the reaction was stirred at ambient temperaturefor another 2 h. The mixture was diluted with EtOAc and filtered througha nylon filter. The solid was washed with EtOAc and MeOH and thefiltrate was concentrated in vacuo providing 0.029 g (58%) of thedesired product as a light tan foam. ES+APCI MS m/z 563.3 [M+H]⁺.

Step G:4-(4-acryloylpiperazin-1-yl)-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(3-morpholinopropoxy)-6,7-dihydropyrido[3,4-d]pyrimidin-8(5H)-one.To a solution of7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(3-morpholinopropoxy)-4-(piperazin-1-yl)-6,7-dihydropyrido[3,4-d]pyrimidin-8(5H)-one(0.028 g, 0.050 mmol) in CH₂Cl₂ (0.50 mL) at −78° C. was addedTriethylamine (0.014 mL, 0.100 mmol). Acryloyl chloride (0.55 mL, 0.055mmol, freshly prepared 0.1M CH₂Cl₂) was added and the reaction was thenstirred for 0.5 h. The mixture was diluted with CHCl₃ and a saturatedaqueous NH₄Cl solution was added. The layers were separated and theaqueous layer was extracted with CHCl₃ (2×10 mL). The combined extractswere dried over Na₂SO₄, filtered and concentrated. The crude product waspurified via column chromatography (4-6% MeOH/DCM) to afford 0.018 g(59%) to provide the title compound as a solid off-white foam. ES+APCIMS m/z 617.3 [M+H]⁺.

Step H.4-(4-acryloylpiperazin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-2-(3-morpholinopropoxy)-6,7-dihydropyrido[3,4-d]pyrimidin-8(5H)-one.To a solution of4-(4-acryloylpiperazin-1-yl)-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(3-morpholinopropoxy)-6,7-dihydropyrido[3,4-d]pyrimidin-8(5H)-one(0.018 g, 0.0292 mmol) in 1/1 MeOH/THF (0.6 mL) was added HCl (0.0486mL, 0.292 mmol, 6 N Aqueous). The mixture was stirred at 35° C. for 7hours. The mixture was diluted with brine and adjusted to pH 8 with asaturated aqueous NaHCO₃ solution. The mixture was extracted with 10%IPA/CHCl₃ (2×10 mL) and CHCl₃ (10 mL). The combined organic layers weredried over Na₂SO₄, filtered and concentrated. The crude material waspurified via column chromatography (6-10% MeOH/DCM) to afford 0.012 g(71%) of the product as an off-white solid. ES+APCI MS m/z 573.3 [M+H]⁺.

Example 122

(R,E)-4-(dimethylamino)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)but-2-en-1-onebis-trifluoroacetate

Steps A-E:(R)-2-((7-(3-(methoxymethoxy)naphthalen-1-yl)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)-N,N-dimethylpropan-1-aminewas synthesized according to the method of Example 8, Step A throughStep E, using (R)-1-(dimethylamino)propan-2-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B.

Step F:(R)-4-(2-((1-(Dimethylamino)propan-2-yl)oxy)-4-(piperazin-1-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)naphthalen-2-oldihydrochloride: To a solution of(R)-2-((7-(3-(methoxymethoxy)naphthalen-1-yl)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)-N,N-dimethylpropan-1-amine(75 mg, 0.15 mmol) in DCM (2.9 mL) was added 6N HCl in iPrOH (247 μl,1.5 mmol) and the mixture was stirred at ambient temperature for 1 h.The reaction mixture was concentrated to dryness to provide(R)-4-(2-((1-(Dimethylamino)propan-2-yl)oxy)-4-(piperazin-1-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)naphthalen-2-oldihydrochloride which was used directly in the next stop. ES+APCI MS m/z463.2 [M+H]⁺.

Step G:(R,E)-4-(Dimethylamino)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)but-2-en-1-onebis-trifluoroacetate: A solution of(R)-4-(2-((1-(Dimethylamino)propan-2-yl)oxy)-4-(piperazin-1-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)naphthalen-2-oldihydrochloride (7 mg, 0.01 mmol), HATU (6.2 mg, 0.02 mmol),(2E)-4-(dimethylamino)but-2-enoic acid (2.1 mg, 0.02 mmol), DIEA (6.9μl, 0.04 mmol) in DCM (131 μl) was stirred at ambient temperature for 1h. The residue was filtered and the filtrate was loaded directly onto aGilson CIS prep HPLC eluting with 5-95% acetonitrile/water with 0.1% TFAadditive. The fractions containing the desired product were concentratedto provide(R,E)-4-(Dimethylamino)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)but-2-en-1-onebis-trifluoroacetate. ES+APCI MS m/z 574.2 [M+H]⁺.

Example 123

1-(4-(2-(2-hydroxy-3-morpholinopropoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using3-morpholinopropane-1,2-diol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 575.2 [M+H]⁺.

Example 124

(R)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(4-fluoro-3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: Benzyl(R)-4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(221 mg, 0.345 mmol) was placed in ACN (2 mL) and the mixture was cooledto 0° C. SelectFluor (183 mg, 0.517 mmol) was added and the reaction wasstirred at room temperature for 30 minutes. Water was added and themixture was extracted with DCM. The organic layers were combined andconcentrated. The resulting residue was purified by reverse phasechromatography (5-95% ACN:water with 0.1% TFA) to provide benzyl(R)-4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(4-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatetrifluoroacetate (48 mg, 0.0729 mmol, 21.1% yield).

Step B:(R)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(4-fluoro-3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-onewas prepared following Example 33, Steps D-F substituting(R)-4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(4-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatetrifluoroacetate for benzyl4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate.ES+APCI MS m/z 535.2 [M+H]⁺.

Example 125

(R)-1-(4-(7-(4-chloro-3-hydroxynaphthalen-1-yl)-2-((1-(dimethylamino)propan-2-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: Benzyl(R)-4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(83 mg, 0.130 mmol) and NCS (21.6 mg, 0.162 mmol) were placed in ACN (2mL) and stirred at room temperature for 3 hours. Water was added and themixture was extracted with DCM (3×15 mL). The organic layers werecombined and concentrated. The resulting residue was purified by reversephase chromatography (5-95% ACN:water with 0.1% TFA) to provide benzyl(R)-4-(7-(4-chloro-3-(methoxymethoxy)naphthalen-1-yl)-2-((1-(dimethylamino)propan-2-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatetrifluoroacetate (17 mg, 0.0252 mmol, 19.4% yield).

Step B:(R)-1-(4-(7-(4-chloro-3-hydroxynaphthalen-1-yl)-2-((1-(dimethylamino)propan-2-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-onewas prepared following Example 33, Steps D-F substituting(R)-4-(7-(4-chloro-3-(methoxymethoxy)naphthalen-1-yl)-2-((1-(dimethylamino)propan-2-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatetrifluoroacetate for benzyl4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylateand using THF as the solvent in Step D. ES+APCI MS m/z 551.2 [M+H]⁺.

Example 126

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(2-(pyridin-2-yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-onetrifluoroacetate

Step A: benzyl4(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(2-(pyridin-2-yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:To a slurry of benzyl4-(2-chloro-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.20 g, 0.35 mmol) in dioxane in a microwave was addedN-ethyl-N-isopropylpropan-2-amine (0.45 g, 3.5 mmol), Cs₂CO₃ (0.34 g,1.0 mmol) and 2-(pyridin-2-yl)ethan-1-ol (0.43 g, 3.5 mmol) and thereaction heated to 15° C. for 1 hr in the microwave. The reaction wasdiluted with EtOAc and washed with water, brine, dried over MgSO₄ andconcentrated in vacuo. The material was chromatographed using a gradientof 0 to 100% EtOAc/DCM as the eluent to give benzyl4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(2-(pyridin-2-yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.16 g, 0.24 mmol, 70% yield).

Step B:4-(4-(piperazin-1-yl)-2-(2-(pyridin-2-yl)ethoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)naphthalen-2-ol:To the solid benzyl4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(2-(pyridin-2-yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.12 g, 0.18 mmol) was added MeOH (20 mL). The solution was degassedwith nitrogen 5 minutes, followed by addition of Pd/C (0.058 g, 0.54mmol). The reaction vessel was evacuated by vacuum and backfilled withH₂. This procedure was performed three times, and after the thirdbackfill the slurry was left to sir under an atmosphere of hydrogen for1 hr. The reaction was again degassed with nitrogen for 5 minutes. Theslurry was next filtered through Celite® and the Celite® was washed withMeOH (100 mL). The combined organic extracts were concentrated andtreated with 10 mL of 1:1 TFA/DCM for 2 hrs. The reaction was againconcentrated in vacuo to give4-(4-(piperazin-1-yl)-2-(2-(pyridin-2-yl)ethoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)naphthalen-2-ol(0.096 g, 0.20 mmol, 110% yield).

Step C:1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(2-(pyridin-2-yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one:To a solution of4-(4-(piperazin-1-yl)-2-(2-(pyridin-2-yl)ethoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)naphthalen-2-ol(0.096 g, 0.20 mmol) in DCM was added Hunig's Base (0.17 mL, 0.99 mmol)and acryloyl chloride (0.018 g, 0.20 mmol) and the reaction stirred for30 minutes at room temperature. The reaction was concentrated in vacuoand the crude material was purified by reverse preparative HPLC to give1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(2-(pyridin-2-yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-onetrifluoroacetate (0.0057 g, 0.011 mmol, 5.3% yield). ES+APCI MS m/z537.2 [M+H]⁺.

Example 127(S)-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

Step A: tert-butyl4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:To a solution of tert-butyl2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (8 g,26.30 mmol) in DMA (263.0 ml, 26.30 mmol) was added benzylpiperazine-1-carboxylate (5.793 g, 26.30 mmol) andN-ethyl-N-isopropylpropan-2-amine (4.721 ml, 26.30 mmol) and thereaction stirred at room temperature for 2 hours. TLC (20% EtOAc/DCM),UV visualization, showed reaction completion. The reaction was nextpoured into water and extracted into DCM. The organics were next washedwith water (2×), brine, dried over MgSO4 and concentrated in vacuo. Theconcentrate was loaded onto a 220 g RegiSep column and chromatagraphedon the CombiFlash (0%-10%, EtOAc:DCM). All fractions containing desiredproduct were combined and concentrated to give tert-butyl4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(9.768 g, 20.02 mmol, 76.11% yield) as a white foam. ES+APCI MS m/z488.2 [M+H]⁺.

Step 13: benzyl4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:tert-butyl4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(9.768 g, 20.02 mmol) was dissolved in dichloromethane (200.2 ml, 20.02mmol) and treated with 2,2,2-trifluoroacetic acid (15.33 ml, 200.2mmol). The reaction mixture stirred at room temp for 4 hours. Aftercompletion the reaction was next concentrated in vacuo and taken up inEtOAc and the organics washed with 1M NaOH (2×), brine, dried over MgSO4and concentrated in vacuo. benzyl4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(7.406 g, 19.09 mmol, 95.39% yield) was used crude in the next reaction.ES+APCI MS m/z 388.2 [M+H]⁺.

Step C: benzyl 4-(2-chloro-7-(3-(methoxymethoxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:To the benzyl4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate,BINAP (0.275 g, 0.442 mmol) and Pd2(dba)3 (0.203 g, 0.221 mmol) underargon was added toluene (221 ml, 11.1 mmol) and the reaction bubbledwith Ar for 10 minutes followed by heating to 100° C. for 10 minutes.The reaction was next cooled to room temperature and benzyl4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(4.29 g, 11.1 mmol) and Sodium Tert-Butoxide (2.13 g, 22.1 mmol) wereadded to the dark solution as solids. Finally,3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (7.44 g,22.1 mmol) was added (as the oil) and the reaction heated to 100° C. for1 hour. The reaction was cooled to room temperature and concentrated invacuo. The concentrate was dissolved with EtOAc and washed with waterand brine. The combined organics were dried over Na2SO4 and concentratedin vacuo. The residue was then loaded on the CombiFlash andchromatographed using 0%→50% Hexane:EtOAc as eluent. Fractionscontaining clean product were combined and concentrated in vacuo toafford benzyl4-(2-chloro-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(2.6 g, 4.53 mmol, 40.9% yield). ES+APCI MS m/z 574.2 [M+H]⁺.

Step D: benzyl(S)-4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:In a microwave tube benzyl4-(2-chloro-7-(3-(methoxymethoxy)naphthalen-b-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(300 mg, 0.523 mmol) was dissolved in Dioxane (6532 μl, 0.523 mmol) andtreated with cesium carbonate (511 mg, 1.57 mmol), Hunig's base (913 μl,5.23 mmol) and N-Methyl-L-prolinol (421 mg, 3.66 mmol). The tube wasthen capped and microwaved at 170° C. for 3 hours. The reaction wasfiltered through GF/F paper. The filtrate was concentrated in vacuo andthe residue loaded onto a 12 g RegiSep gold column and chromatagraphedon the CombiFlash (0%-15%, DCM:MeOH). All fractions containing cleanproduct were combined and concentrated in vacuo to give benzyl(S)-4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((I-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(220 mg, 0.337 mmol, 64.5% yield). ES+APCI MS m/z 653.3 [M+H]⁺.

Step E:(S)-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine:A solution of benzyl(S)-4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(220 mg, 0.337 mmol) in EtOH (3370 μl, 0.337 mmol) and THF (3370 μl,0.337 mmol) was purged with N2 for 5 minutes. To this solution was addedPalladium on carbon (179 mg, 0.0843 mmol) (Degussa Type, 10 wt %, 50%H2O), and was immediately capped and purged with N2 for an additional 5min. The solution then stirred under H2 introduced via vacuum followedby balloon pressure. The mixture was then stirred at ambient temperatureover night. LC/MS showed reaction completion. The mixture was dilutedwith MeOH and filtered through packed celite. The filtrate was thenconcentrated in vacuo and(S)-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine(91 mg, 0.175 mmol, 52.1% yield) was taken forward as the crude. ES+APCIMS m/z 519.3 [M+H]⁺.

Step F:(S)-1-(4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one:To a suspension of(S)-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine(92 mg, 0.18 mmol) in dichloromethane (1774 μl, 0.18 mmol) at ambienttemperature was added Acryloyl Chloride (1774 μl, 0.18 mmol) followed byHunig's base (62 μl, 0.35 mmol). The reaction was then stirred atambient temperature for 1 hour. The mixture was then concentrated andloaded onto a 4 g RegiSep gold column and chromatagraphed on theCombiFlash (0%-15%, DCM:MeOH). All fractions containing clean productwere combined and concentrated in vacuo to give(S)-1-(4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one(74 mg, 0.13 mmol, 73% yield). ES+APCI MS m/z 573.3 [M+H]⁺.

Step G:(S)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one:(S)-1-(4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one(74 mg, 0.13 mmol) was dissolved in methanol (4307 μl, 0.13 mmol) andtreated with hydrogen chloride (1077 μl, 6.5 mmol) (aq). The reactionstirred at 55° C. for 1 hour. The reaction mixture was concentrated invaccuo and was resuspended in 1.5 mL of MeOH. The suspension was loadedon to the Gilson (prep HPLC), which was eluted with 5→95% ACN/0.1% TFAin water/0.1% TFA. All fractions containing clean product were combinedand lyophilized overnight to give(S)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one(26 mg, 0.049 mmol, 38% yield). ES+APCI MS m/z 529.3 [M+H]⁺.

Example 1281-(4-(2-(3-(dimethylamino)azetidin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: benzyl4-(2-(3-(dimethylamino)azetidin-1-yl)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:To a solution of benzyl4-(2-chloro-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.20 g, 0.35 mmol) in dioxanes was added N,N-dimethylazetidin-3-aminehydrochloride (0.24 g, 1.7 mmol) and N-ethyl-N-isopropylpropan-2-amine(0.45 g, 3.5 mmol) and the reaction was heated to 80° C. for 72 hrs. Thereaction was concentrated in vacuo and the residue chromatographed using0→20% MeOH/DCM as eluent to give benzyl4-(2-(3-(dimethylamino)azetidin-1-yl)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.25 g, 105%). ES+APCI MS m/z 638.3 [M+H]⁺.

1-(4-(2-(3-(dimethylamino)azetidin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-onewas made according to Example 127 substituting benzyl4-(2-(3-(dimethylamino)azetidin-1-yl)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatefor benzyl(S)-4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatein step E. ES+APCI MS m/z 514.2 [M+H]⁺.

Example 1291-[4-[7-(3-hydroxy-1-naphthyl)-2-[(1R)-1-[(2R)-1-methylpyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: tert-butyl (2R)-2-[(1-hydroxyethyl]pyrolidine-1-carboxylate: Amixture of BH₃-Me₂S (10 M, 549 uL) and(3aS)-1-methyl-3,3-diphenyl-3a,4,5,6-tetrahydropyrrolo[1,2-c][1,3,2]oxazaborole(1.00 M, 844 uL,) in THF (10 mL) was stirred at 15° C. for 1 hour. Tothe mixture was added a solution of tert-butyl(2R)-2-acetylpyrrolidine-1-carboxylate (0.90 g, 4.22 mmol) in THF (10mL) and the mixture stirred at 15° C. for 1 hour. The mixture wasquenched by addition of methanol (2.00 mL) and the reaction concentratedunder vacuum. The residue was purified by column chromatography (SiO₂,petroleum ether/ether acetate 50/1-5/1) to give tert-butyl(2R)-2-[(1R)-1-hydroxyethyl]pyrrolidine-1-carboxylate (0.60 g, 2.79mmol, 66.0% yield) as a colorless oil. ¹H NMR (400 MHz, CD₃OD) δ=5.18(br s, 1H), 3.73 (dt, J=4.8, 8.0 Hz, 1H), 3.70-3.43 (m, 2H), 3.28 (td,J=6.64, 10.8 Hz, 1H), 1.96 (qd, J=7.2, 12.8 Hz, 1H), 1.89-1.68 (m, 2H),1.62 (br s, J=6.4 Hz, 1H), 1.47 (s, 9H), 1.15 (d, J=6.0 Hz, 3H).

Step B: benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-1-[(2R)-1-tert-butoxycarbonylpyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.70 g, 1.08 mmol) and tert-butyl(2R)-2-[(1R)-1-hydroxyethyl]pyrrolidine-1-carboxylate (349 mg, 1.62mmol) in THF (10 mL) was added t-BuONa (312 mg, 3.24 mmol) and themixture stirred at 10° C. for 1 hour. The mixture was diluted with water(10 mL) and the aqueous layer extracted with ethyl acetate (3×10 mL).The combined organics were washed brine (20 mL), dried over Na₂SO₄,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography (SiO₂, petroleum ether/ether acetate=3/1) to givebenzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-1-[(2R)-1-tert-butoxycarbonylpyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.35 g, 412 umol, 38.1% yield) as a yellow solid. ES+APCI MS m/z 799.4[M+H]⁺.

Step C: benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-1-[(2R)-pyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:A mixture of benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-1-[(2R)-1-tert-butoxycarbonylpyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.30 g, 375 umol) and TFA (642 mg, 5.63 mmol, 417 uL) indichloromethane (0.42 mL) was stirred at 10° C. for 1 hour. The mixturewas concentrated under vacuum to give benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-1-[(2R)-pyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(305 mg) LCMS [M+1]: ES+APCI MS m/z 699.2 [M+H]⁺.

Step D: benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-1-[(2R)-1-methylpyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:A mixture of benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-1-[(2R)-pyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.30 g, crude), formaldehyde (210 mg, 1.85 mmol, 192 uL, 37% water) andAcOH (22.16 mg, 369 umol, 21.1 uL) in methanol (3.00 mL) was stirred at15° C. for 0.5 hours. To the mixture was added NaBH₃CN (58.0 mg, 923umol) and the mixture stirred at 15° C. for 48 hours. The mixture wasquenched by addition of H₂O (5 mL) at 0° C., and the aqueous layerextracted with ether acetate (3×10 mL) The combined organics were washedwith brine (15.0 mL), dried over Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by reverse phase flash [water (0.10%Formic Acid)/acetonitrile] to give benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-1-[(2R)-1-methylpyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.10 g, 126 umol) as a yellow oil. ES+APCI MS m/z 713.4 [M+H]⁺.

Step E:4-[2-[(1R)-1-[(2R)-1-methylpyrrolidin-2-yl]ethoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol:Ammonia was bubbled into methanol (3 mL) at −78° C. for 30 minutes.benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-1-[(2R)-1-methylpyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.09 g, 126 umol) and dry 10% Pd/C (0.10 g) were next added and themixture stirred at 10° C. for 1 hour under H₂ (15 psi). The reaction wasfiltered and the filtrate was concentrated wider vacuum to give4-[2-[(1R)-1-[(2R)-1-methylpyrrolidin-2-yl]ethoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol(0.04 g, crude) as a yellow oil. ES+APCI MS m/z 489.2 [M+H]⁺.

Step F:1-[4-[7-(3-hydroxy-1-naphthyl)-2-[(1R)-1-[(2R)-1-methylpyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a solution of 4-[2-[(1R)-1-[(2R)-1-methylpyrrolidin-2-yl]ethoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol(0.04 g) and Et₃N (124 mg, 1.23 mmol, 171 uL) in DCM (2.00 mL) at −40°C. was added prop-2-enoyl prop-2-enoate (7.23 mg, 57.3 umol) and thereaction stirred at −40° C. for 0.5 h. The mixture was quenched byaddition of methanol (0.10 mL) and concentrated under vacuum. Theresidue was purified by prep-HPLC (column. Phenomenex Synergi C18150*25*10 um; mobile phase: [water (0.225% Formic Acid)-ACN]; B %:10%-37% over 10 minutes) to give1-[4-[7-(3-hydroxy-1-naphthyl)-2-[(1R)-1-[(2R)-1-methylpyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(9.13 mg, 15.5 umol) as a yellow solid. ES+APCI MS m/z 543.4 [M+H]⁺.

Example 1301-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-onewas prepared following Example 129 substituting(3aR)-1-methyl-3,3-diphenyl-3a,4,5,6-tetrahydropyrrolo[1,2-c][1,3,2]oxazaborole for(3aS)-1-methyl-3,3-diphenyl-3a,4,5,6-tetrahydropyrrolo[1,2-c][1,3,2]oxazaborolein Step A while also substituting tert-butyl(2S)-2-acetylpyrrolidine-1-carboxylate for tert-butyl(2R)-2-acetylpyrrolidine-1-carboxylate in Step A. ES+APCI MS m/z 543.4[M+H]⁺.

Example 1311-[4-[2-[(1R)-2-[ethyl(methyl)amino]-1-methyl-ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: (2R)-1-[ethyl(methyl)amino]propan-2-ol: (2R)-2-methyloxirane(540 mg, 9.31 mmol, 651 uL) was added to N-methylethanamine (500 mg,8.46 mmol, 725 uL) in MeOH (10 mL). The resulting solution was stirredat 80° C. for 3 hours in a sealed tube. Upon completion, the mixture wasconcentrated under vacuum to give (2R)-[ethyl(methyl)amino]propan-2-ol(260 mg, crude) as a light yellow oil which was used directly in thenext step without further purification.

Step B: benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-2-[ethyl(methyl)amino]-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of (2R)-1-[ethyl(methyl)amino]propan-2-ol (217 mg, 1.85mmol) in toluene (20 mL) was added benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(400 mg, 617 umol), Pd₂(dba)₃ (56.6 mg, 61.8 umol), BINAP (76.9 mg, 124umol) and NaOtBu (178 mg, 1.85 mmol,) and the mixture de-gassed with N2for 15 minutes and then heated to 90° C. for 16 hours under N₂. Uponcompletion, the reaction mixture was filtered and the filtrateconcentrated under vacuum. The residue was purified by reversed-phasechromatography to give benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-2-[ethyl(methyl)amino]-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(110 mg, 153 umol, 24.8% yield, 97.5% purity). ES+APCI MS m/z 701.4[M+H]⁺.

Step C:4-[2-[(1R)-2-[ethyl(methyl)amino]1-methyl-ethoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol:To a solution of benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-2-[ethyl(methyl)amino]-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(100 mg, 143 umol) in MeOH (3.00 mL) was added HCl/MeOH (4 M, 143 uL),followed by Pd(OH)₂/C (50 mg) under N₂. The suspension was degassedunder vacuum and purged with H₂ several times. The mixture was stirredunder H₂ (15 psi) at 40° C. for 4 hours. Upon completion, the reactionmixture was filtered and the filtrate concentrated to give4-[2-[(1R)-2-[ethyl(methyl)amino]-1-methyl-ethoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol(76.0 mg, 125 umol, 87.5% yield, 90.3% purity, 2 HCl) which was useddirectly in the next step without further purification. ES+APCI MS m/z477.2 [M+H]⁺.

Step D:1-[4-[2-[(1R)-2-[ethyl(methyl)amino]-1-methyl-ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a solution of4-[2-[(1R)-2-[ethyl(methyl)amino]-1-methyl-ethoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol(70 mg, 127 umol, 2 HCl) and DIEA (98.8 mg, 764 umol, 133 uL) in DCM(1.50 mL) was added prop-2-enoyl prop-2-enoate (12.9 mg, 102 umol)dropwise at −50° C. The mixture was stirred at −40 to −20° C. for 30minutes. Upon completion, the mixture was quenched by addition of MeOH(17.0 mg) and concentrated under vacuum. The residue was diluted withwater (1 mL) and extracted with DCM (3×6 mL). The organic layers weredried over Na₂SO₄ and concentrated under vacuum. The residue waspurified by prep-HPLC (column: Phenomenex Gemini 150*25 mm*10 um; mobilephase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 48%-78%, 10 min)to give1-[4-[2-[(1R)-2-[ethyl(methyl)amino]-1-methyl-ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(9.23 mg, 17.2 umol, 13.5% yield, 98.7% purity) as a yellow solid.ES+APCI MS m/z 531.3 [M+H]⁺.

Example 1321-[4-[2-[(1-cyclohexylpyrrolidin-3-yl)methoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: 1-cyclohexylpyrrolidine-3-carboxylate: To a solution of methylpyrrolidine-3-carboxylate (1.00 g, 6.04 mmol, HCl) and DIEA (780 mg,6.04 mmol, 1.05 mL) was added cyclohexanone (652 mg, 6.64 mmol, 686 uL)and HOAc (725 mg, 12.1 mmol, 691 uL) at 0° C. The reaction mixture wasstirred at 0° C. for 0.5 h. To the reaction mixture was added NaBH(OAc)₃(3.84 g, 18.12 mmol) in portions at 0° C. The reaction mixture wasstirred at 0 to 15° C. for 12 hours. Upon completion, the reactionmixture was quenched by addition of water (5 mL) and organicsconcentrated under vacuum. The aqueous layer was extracted with DCM (10mL×2) and the pH adjusted with sat NaHCO₃ (10 mL) and Na₂CO₃ (2 mL) topH>8. The organic layers were combined, dried over Na₂SO₄ andconcentrated under vacuum. The residue was triturated withMTBE/Petroleum Ether (1:3, 20 mL) and the filtrate concentrated undervacuum to give methyl 1-cyclohexylpyrrolidine-3-carboxylate (1.00 g,4.73 mmol, 78.4% yield) as brown oil. ES+APCI MS m/z 212.2 [M+H]⁺.

Step B: (1-cyclohexylpyrrolidin-3-yl)methanol: To a solution of methyl1-cyclohexylpyrrolidine-3-carboxylate (1.00 g, 4.73 mmol) in THF (20 mL)was added LiAlH₄ (413 mg, 10.9 mmol) at −10° C. The reaction mixture wasstirred at −10° C. for 0.5 hour. The reaction mixture was quenched byaddition of saturated Na₂SO₄ (2 mL) and mixture filtered and the filtercake washed with THF (3×50 mL). The combined organics were concentratedunder vacuum to give: (1-cyclohexylpyrrolidin-3-yl)methanol (800 mg,4.36 mmol, 92.3% yield) as a colorless oil. ¹H NMR (400 MHz,CHLOROFORM-d) δ=3.71 (dd, J=4.1, 10.0 Hz, 1H), 3.53 (dd, J=4.4, 10.0 Hz,1H), 2.90 (dt, J=4.4, 8.8 Hz, 1H), 2.74 (dd, J=3.2, 8.8 Hz, 1H), 2.53(dd, J=6.8, 8.8 Hz, 1H), 2.36-2.24 (m, 2H), 2.04-1.93 (m, 2H), 1.90 (brs, 2H), 1.78-1.64 (m, 3H), 1.61-1.52 (m, 1H), 1.33-1.12 (m, 5H)

1-[4-[2-[(1-cyclohexylpyrrolidin-3-yl)methoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-onewas prepared following Example 131 substituting(1-cyclohexylpyrrolidin-3-yl)methanol for(2R)-1-[ethyl(methyl)amino]propan-2-ol in Step B. ES+APCI MS m/z 597.4[M+H]⁺.

Example 1331-[4-[7-(3-hydroxy-1-naphthyl)-2-(3-morpholinopropylamino)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-(3-morpholinopropylamino)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:A solution of benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(400 mg, 617 umol) and 3-morpholinopropan-1-amine (534 mg, 3.70 mmol,540 uL) in DMSO (4.00 mL) was heated to 100° C. for 12 hours. Uponcompletion, the mixture was diluted with water (4 mL) and extracted withEtOAc (3×20 mL). The organic layers were washed with brine (30 mL),dried over Na₂SO₄ and concentrated under vacuum. The residue waspurified by column chromatography over Al₂O₃ eluting with EthylAcetate/Petroleum Ether (20→100%) to give benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-(3-morpholinopropylamino)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(245 mg, 320 umol, 51.8% yield, 95.0% purity) as a yellow oil. ES+APCIMS m/z 728.6 [M+H]⁺.

1-[4-[7-(3-hydroxy-1-naphthyl)-2-(3-morpholinopropylamino)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-onewas prepared following Example 131 substituting benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-(3-morpholinopropylamino)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylatefor benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-2-[ethyl(methyl)amino]-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylatein Step C. ES+APCI MS m/z 558.6 [M+H]⁺.

Example 134(R)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(piperidin-3-ylmethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: tert-butyl (3R)-3-(hydroxymethyl)piperidine-1-carboxylate: TEA(1.76 g, 17.4 mmol, 2.42 mL) was added to a solution of[(3R)-3-piperidyl]methanol (1.0 g, 8.68 mmol) in THF (25.0 mL), followedby the addition of a solution of Boc₂O (1.89 g, 8.68 mmol, 1.99 mL) inTHF (5 mL) at 15° C. The mixture was stirred at 15° C. for 12 hours. Thesolvent was removed under vacuum and the residue dissolved in ethylacetate (50 ml) and H₂O (30 mL). The solution was acidified with HCl (6M) to pH˜6 and the layers separated. The organics were washed with brine(3×50 mL) and the combined organics concentrated to dryness to givetert-butyl (3R)-3-(hydroxymethyl)piperidine-1-carboxylate (1.68 g, 7.80mmol, 89.9% yield, 100% purity) as colorless crystals. ¹H NMR (400 MHz,chloroform-d) δ=3.73 (br s, 2H), 3.51 (br d, J=6.8 Hz, 2H), 3.05 (br s,2H), 1.83-1.71 (m, 2H), 1.62 (br s, 1H), 1.46 (s, 9H), 1.44-1.37 (m,1H), 1.35-1.22 (m, 1H).

Step B: benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(3R)-1-tert-butoxycarbonyl-3-piperidyl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of tert-butyl (3R)-3-(hydroxymethyl)piperidine-1-carboxylate (332 mg, 1.54 mmol) in THF (5 mL) was addedt-BuONa (223 mg, 2.32 mmol). A solution of benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 772 umol) in THF (5 mL) was next added and the mixture stirredat 0° C. for 1 hour. The reaction mixture was filtered and concentratedunder reduced pressure and the residue purified by column chromatographyeluting with Petroleum ether/Ethyl Acetate (10/1 to 3/1) to give benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(3R)-1-tert-butoxycarbonyl-3-piperidyl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(510 mg, 628 umol, 81.4% yield, 98.4% purity) as a white solid. ES+APCIMS m/z 799.4 [M+H]⁺.

Step C: tert-butyl(3R)-3-[[7-(3-hydroxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]piperidine-1-carboxylate:A solution of benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(3R)-1-tert-butoxycarbonyl-3-piperidyl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(250 mg, 313 umol) in MeOH (5 mL) was purged with NH₃ (10%, w/w) andthen 10% Pd/C (50 mg) was added. The suspension was degassed undervacuum and the mixture stirred under H₂ (15 psi) at 15° C. for 12 hours.The reaction mixture was filtered and concentrated under reducedpressure to dryness to give tert-butyl(3R)-3-[[7-(3-hydroxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]piperidine-1-carboxylate(126 mg, 211 umol, 67.4% yield, 96.2% purity) as a colorless oil.ES+APCI MS m/z 575.5 [M+H]⁺.

Step D: tert-butyl(3R)-3-[[7-(3-hydroxy-1-naphthyl)-4-(4-prop-2-enoylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]piperidine-1-carboxylate:To a solution of tert-butyl(3R)-3-[[7-(3-hydroxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]piperidine-1-carboxylate(126 mg, 219 umol) and TEA (33.3 mg, 329 umol, 45.8 uL) in DCM (5.0 mL)was added prop-2-enoyl prop-2-enoate (24.9 mg, 197 umol) dropwise at−40° C. and the reaction stirred for 30 minutes at −40′C. The reactionmixture was quenched by addition MeOH (0.5 mL) and concentrated todryness. The residue was dissolved into EtOAc (50 mL) and H₂O (20 mL).The resulting solution was acidified with HCl (1 M) to pH˜6 and thelayers separated. The combined organics were dried over Na₂SO₄, filteredand concentrated under reduced pressure to givetert-butyl(3R)-3-[[7-(3-hydroxy-1-naphthyl)-4-(4-prop-2-enoylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]piperidine-1-carboxylate(120 mg, 172 umol, 78.5% yield, 90.2% purity) as a yellow oil, which wasused directly for next step without further purification. ES+APCI MS m/z629.6 [M+H]⁺.

Step E: 1-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(3R)-3-piperidyl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a solution oftert-butyl(3R)-3-[[7-(3-hydroxy-1-naphthyl)-4-(4-prop-2-enoylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]piperidine-1-carboxylate(120 mg, 191 umol) in DCM (3.0 mL) was added TFA (326 mg, 2.86 mmol, 212uL) at 0° C. The mixture was stirred at 15° C. for 2 hours under N₂atmosphere. The reaction mixture was basified with NH₃ (30% in water,three drops) and concentrated to dryness. The residue was purified byprep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase:[water (0.225% Formic Acid)-ACN]; B %: 5%-35%, 10 min) to give1-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(3R)-3-piperidyl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(24.5 mg, 38.9 umol, 20.4% yield) as a yellow solid. ES+APCI MS m/z529.4 [M+H]⁺.

Example 1351-[4-[2-[3-(4-acetylpiperazin-1-yl)propoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: 1-[4-(3-hydroxypropyl)piperazin-1-yl]ethanone: To a solution of1-piperazin-1-ylethanone (2.00 g, 15.6 mmol) and K₂CO₃ (4.31 g, 31.2mmol) in CH₃CN (50.0 mL) was added 3-bromopropan-1-ol (3.25 g, 23.4mmol). The mixture was stirred at 80° C. for 5 hours. The solid wasfiltered and the filtrate was evaporated to give1-[4-(3-hydroxypropyl)piperazin-1-yl]ethanone (2.00 g, 10.7 mmol, 68.8%yield) as a colorless oil.

1-[4-[2-[3-(4-acetylpiperazin-1-yl)propoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-onewas prepared following Example 131 substituting1-[4-(3-hydroxypropyl)piperazin-1-yl]ethanone for benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-2-[ethyl(methyl)amino]-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylatein Step C. ES+APCI MS m/z 600.3 [M+H]⁻.

Example 1361-[4-[7-(3-hydroxy-1-naphthyl)-2-[2-(3-methoxypyrrolidin-1-yl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: 2-(3-methoxypyrrolidin-1-yl)ethanol: To a solution of3-methoxypyrrolidine (450 mg, 3.27 mmol, HCl) and 2-bromoethanol (408mg, 3.27 mmol) in CH₃CN (10 mL) was added K₂CO₃ (1.36 g, 9.81 mmol) Themixture was stirred at 80° C. for 3 hours. The solid was filtered andthe filtrate was evaporated to give 2-(3-methoxypyrrolidin-1-yl)ethanol(450 mg, 3.10 mmol, 94.8% yield) as a colorless oil.

Step B: benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(3-methoxypyrrolidin-1-yl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:A mixture of benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 771 umol), 2-(3-methoxypyrrolidin-1-yl)ethanol (224 mg, 1.54mmol), and t-BuONa (222 mg, 2.32 mmol) in toluene (10 mL) was stirred at20° C. for 1 hour under N₂ atmosphere. The mixture was cooled to 0° C.and HCl (2M) was added until pH˜7. The mixture was filtered and filtratewas concentrated in vacuum. The residue was purified by columnchromatography using 0→10% MeOH/DCM as eluent to give benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(3-methoxypyrrolidin-1-yl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(110 mg, 147.9 umol, 19.1% yield) ES+APCI MS m/z 729.2 [M+H]⁺.

1-[4-[7-(3-hydroxy-1-naphthyl)-2-[2-(3-methoxypyrrolidin-1-yl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-onewas prepared following Example 131 substituting benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(3-methoxypyrrolidin-1-yl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylatefor benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-2-[ethyl(methyl)amino]-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylatein Step C. ES+APCI MS m/z 559.3 [M+H]⁺.

Example 1371-[4-[7-(3-hydroxy-1-naphthyl)-2-[3-(3-methoxypyrrolidin-1-yl)propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: (3-methoxypyrrolidin-1-ylpropan-1-ol: To a solution of3-methoxypyrrolidine (500 mg, 3.63 mmol, HCl) and 3-bromopropan-1-ol(505 mg, 3.63 mmol) in CH₃CN (10 mL) was added K₂CO₃ (1.51 g, 10.9mmol). The mixture was stirred at 20° C. for 5 hours. The solid wasfiltered and the filtrate was evaporated to give3-(3-methoxypyrrolidin-1-ylpropan-1-ol (540 mg, 3.39 mmol, 93.3% yield).

1-[4-[7-(3-hydroxy-1-naphthyl)-2-[3-(3-methoxypyrrolidin-1-yl)propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-onewas prepared following Example 131 substituting(3-methoxypyrrolidin-1-yl)propan-1-ol for(2R)-1-[ethyl(methyl)amino]propan-2-ol in Step B. ES+APCI MS m/z 573.3[M+H]⁺.

Example 1381-[4-[2-[2-(3,3-difluoroazetidin-1-yl)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: 2-(3,3-difluoroazetidin-1-yl)ethanol: To a solution of3,3-difluoroazetidine (500 mg, 3.86 mmol, HCl) and 2-bromoethanol (482mg, 3.86 mmol, 274 uL) in CH₃CN (10 mL) was added K₂CO₃ (1.60 g, 11.5mmol) and the reaction stirred at 80° C. for 16 hours. The reaction wasfiltered and the filtrate evaporated to give2-(3,3-difluoroazetidin-1-yl)ethanol (300 mg, 2.19 mmol, 56.7% yield).

1-[4-[2-[2-(3,3-difluoroazetidin-1-yl)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-onewas prepared following Example 131 substituting give2-(3,3-difluoroazetidin-1-yl)ethanol for(2R)-1-[ethyl(methyl)amino]propan-2-ol in Step B. ES+APCI MS m/z 551.4[M+H]⁺.

Example 1391-[4-[2-[2-(3,3-difluoropyrrolidin-1-yl)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: Methyl 2-(3,3-difluoropyrrolidin-1-yl)acetate: To a suspensionof methyl 2-bromoacetate (1.17 g, 7.67 mmol, 723 uL) in DCM (10 mL)cooled to 0° C. was added TEA (1.76 g, 17.4 mmol, 2.42 mL) and3,3-difluoropyrrolidine (1.00 g, 6.97 mmol, HCl) and the reactionmixture stirred at 20° C. for 16 hours. The reaction was filtered andfiltrate was evaporated. The residue was purified by columnchromatography with 0.5%→20% MeOH/DCM as eluent to give methyl2-(3,3-difluoropyrrolidin-1-yl)acetate (580 mg, 3.24 mmol, 46.4% yield).¹H NMR (400 MHz, chloroform-d) δ 3.73 (s, 3H), 3.38 (s, 2H), 3.11 (t,J=13.6 Hz, 2H), 2.92 (t, J=6.8 Hz, 2H), 2.36-2.26 (m, 2H).

Step B: 2-(3,3-difluoropyrrolidin-1-yl)ethanol: To a solution of LiAlH₄(184 mg, 4.86 mmol) in THF (5.0 mL) was added a solution of methyl2-(3,3-difluoropyrrolidin-1-yl)acetate (580 mg, 3.24 mmol) in THF (5.0mL) dropwise at 0° C. The mixture was warmed to 20° C. and stirred for 3hours. The mixture was quenched by addition of saturated aqueous sodiumsulfate solution (1.50 mL) The reaction was filtered and the filtratedwas concentrated under vacuum to give2-(3,3-difluoropyrrolidin-1-yl)ethanol (330 mg, 2.18 mmol, 67.4% yield)as a colourless oil. ¹H NMR (400 MHz, chloroform-d) δ=3.64 (t, J=5.2 Hz,2H), 2.97 (t, J=13.2 Hz, 2H), 2.82 (t, J=7.2 Hz, 2H), 2.68 (t, =5.2 Hz,2H), 2.49 (br. s, 1H), 2.34-2.24 (m, 2H).

1-[4-[2-[2-(3,3-difluoropyrrolidin-1-yl)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-onewas prepared following Example 131 substituting2-(3,3-difluoropyrrolidin-1-yl)ethanol for(2R)-1-[ethyl(methyl)amino]propan-2-ol in Step B. ES+APCI MS m/z 565.3[M+H]⁺.

Example 1402-[3-[[7-(3-hydroxy-1-naphthyl)-4-(4-prop-2-enoylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidin-1-yl]-N,N-dimethyl-acetamide

Step A: methyl1-[2-(dimethylamino)-2-oxo-ethyl]pyrrolidine-3-carboxylate: A solutionof methyl pyrrolidine-3-carboxylate (1.00 g, 6.04 mmol, HCl) and NaHCO3(1.01 g, 12.1 mmol, 470 uL) in ACN (200.0 mL) was stirred at 10° C. for5 minutes. A solution of 2-bromo-N,N-dimethyl-acetamide (1.00 g, 6.04mmol) in ACN (5.00 mL) was next added at 10° C. and the reaction stirredat 10° C. for 6 hours followed by and stirring at 50° C. for 2 hours.The mixture was filtered and and solids washed with DCM (3×15 ml). Thefiltrate was concentrated under vacuum and the residue purified bycolumn chromatography using 0→10% MeOH/DCM as eluent to to give methyl1-[2-(dimethylamino)-2-oxo-ethyl]pyrrolidine-3-carboxylate (480 mg, 2.02mmol, 33.4% yield).

Step B: 2-[3-(hydroxymethyl)pyrrolidin-1-yl]-N,N-dimethyl-acetamide: Toa solution of methyl1-[2-(dimethylamino)-2-oxo-ethyl]pyrrolidine-3-carboxylate (500 mg, 2.33mmol) in THF (10 mL) was added LiAlH₄ (203 mg, 5.36 mmol) at −60° C. andthe reaction mixture stirred at −60° C. for 10 minutes. The reactionmixture was quenched by the addition of saturated Na₂SO₄ (0.4 mL) andand the slurry was filtered. The filter cake was washed with THF (3×50mL) and the filtrate concentrated under vacuum to give2-[3-(hydroxymethyl)pyrrolidin-1-yl]-N,N-dimethyl-acetamide (400 mg,2.15 mmol, 92.2% yield) as a brown oil. ES+APCI MS m/z 187.1 [M+H]⁺.

Step C: benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[1-[2-(dimethylamino)-2-oxo-ethyl]pyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:A mixture of benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 772 umol),2-[3-(hydroxymethyl)pyrrolidin-1-yl]-N,N-dimethyl-acetamide (216 mg,1.16 mmol) and NaOBu-t (148 mg, 1.54 mmol) in toluene (10 mL) wasstirred at 15° C. for 15 minutes. The reaction mixture was purifieddirectly by silica gel chromatography using 20→100% EtOAc/PetroleumEther to give benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[1-[2-(dimethylamino)-2-oxo-ethyl]pyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(310 mg, 395 umol, 51.1% yield, 98% purity) as a brown solid. ES+APCI MSm/z 770.4 [M+H]⁺.

2-[3-[[7-(3-hydroxy-1-naphthyl)-4-(4-prop-2-enoylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidin-1-yl]-N,N-dimethyl-acetamidewas prepared following Example 131 substituting benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[1-[2-(dimethylamino)-2-oxo-ethyl]pyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylatefor benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-2-[ethyl(methyl)amino]-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylatein Step C. ES+APCI MS m/z 600.3 [M+H]⁺.

Example 1411-[4-[2-[[1-(2-hydroxyethyl)pyrrolidin-3-yl]methoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: methyl pyrrolidine-3-carboxylate: To a solution of1-(tert-butyl) 3-methyl pyrrolidine-1,3-dicarboxylate (10.0 g, 43.6mmol) in DCM (50 mL) was added HCl/dioxane (4 M, 109 mL) at 0° C. andstirred at 0° C. for 1 hour. The mixture was concentrated under vacuumto give methyl pyrrolidine-3-carboxylate (7.00 g, crude, HCl) as brownoil. ¹H NMR (400 MHz, methanol-d₄) δ=3.77 (s, 3H), 3.56-3.53 (m, 2H),3.41-3.37 (m, 3H), 2.40-2.24 (m, 2H).

Step B: methyl 1-(2-benzyloxyethyl)pyrrolidine-3-carboxylate: A solutionof methyl pyrrolidine-3-carboxylate (3.0 g, 18.1 mmol, HCl), Cs₂CO₃(17.7 g, 54.3 mmol) and KI (301 mg, 1.81 mmol) in MeCN (60 mL) wasstirred at 15° C. for 5 min. Then a solution of2-bromoethoxymethylbenzene (4.67 g, 21.7 mmol, 3.43 mL) in ACN (15 mL)was added to the mixture at 15° C. and stirred at 15° C. for 1 hour. Themixture was next warmed to 50° C. and stirred at 50° C. for 12 hours.The reaction mixture was filtered and the filter cake washed with DCM(3×30 mL) and the filtrate concentrated under vacuum. The residue waspurified by prep-HPLC (column: Phenomenex luna C18 250*50 mm*10 um;mobile phase: [water (0.1% TFA)-ACN]; B %: 10 ACN %-40 ACN %, 30 min 40%min) to give methyl 1-(2-benzyloxyethyl)pyrrolidine-3-carboxylate (1.48g, 5.06 mmol, 27.9% yield, 90.0% purity) as brown oil. ¹H NMR (400 MHz,chloroform-d) δ=7.36-7.28 (m, 5H), 4.56 (s, 2H), 3.70 (s, 3H), 3.61-3.58(t, J=6.0 Hz, 2H), 3.02-3.00 (m, 2H), 2.78-2.67 (m, 4H), 2.58-2.49 (m,1H), 2.11-2.08 (m, 2H)

Step C: (1-(2-(benzyloxy)ethyl)pyrrolidin-3-yl)methanol: To the solutionof methyl 1-(2-benzyloxyethyl)pyrrolidine-3-carboxylate (1.38 g, 5.24mmol) in THF (27 mL) was added LiAlH₄ (457 mg, 12 mmol) at −10° C. andstirred at −10° C. for 0.5 hour. The reaction mixture was quenched bysaturated Na₂SO₄ (1 mL) and filtered, the filter cake was washed withTHF (5×30 mL), the filtrate was concentrated under vacuum to give(1-(2-(benzyloxy)ethyl)pyrrolidin-3-yl)methanol (1.30 g, 3.31 mmol,63.3% yield, 60.0% purity) as brown oil. ES+APCI MS m/z 236.1 [M+H]⁺.

1-[4-[2-[[1-(2-hydroxyethyl)pyrrolidin-3-yl]methoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-onewas prepared following Example 136 substituting(1-(2-(benzyloxy)ethyl)pyrrolidin-3-yl)methanol for2-(3-methoxypyrrolidin-1-yl)ethanol in Step B. ES+APCI MS m/z 559.3[M+H]⁺.

Example 1421-[4-[2-(2-hydroxyethoxy)-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

1-[4-[2-(2-hydroxyethoxy)-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-onewas prepared following Example 136 substituting2-[tert-butyl(dimethyl)silyl]oxyethanol for2-(3-methoxypyrrolidin-1-yl)ethanol in Step B. ES+APCI MS m/z 476.2[M+H]⁺.

Example 1431-[4-[2-(2,3-dihydroxypropoxy)-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

1-[4-[2-(2,3-dihydroxypropoxy)-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-onewas prepared following Example 136 substituting(2,2-dimethyl-1,3-dioxolan-4-yl)methanol for2-(3-methoxypyrrolidin-1-yl)ethanol in Step B. ES+APCI MS m/z 506.3[M+H]⁺.

Example 144(S)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-(2-methoxyethyl)pyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: tert-butyl (2S)-2-(benzyloxymethyl)pyrrolidine-1-carboxylate: Toa slurry of NaH (2.38 g, 59.6 mmol, 60% purity) in THF (50 mL) was addeda solution of tert-butyl (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate(10 g, 49.69 mmol) in THF (50 mL) at 0° C. and the mixture was stirredat 10° C. for 1 hour. Bromoethylbenzene (12.8 g, 74.5 mmol, 8.85 mL) wasadded dropwise at 0° C. and the mixture was stirred at 10° C. for 16hours. The mixture was quenched by addition of saturated aqueous ammoniachloride solution (20 mL) and then diluted with ethyl acetate (200 mL)and water (100 mL). The separated organic layer was washed with water(100 mL) and brine (100 mL), dried over sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by columnchromatography over silica gel (petroleum ether/ethyl acetate 100/1 to5/1) to give tert-butyl(2S)-2-(benzyloxymethyl)pyrrolidine-1-carboxylate (8.2 g, 28.06 mmol,56.5% yield, 99.7% purity) was obtained as a colorless oil. ES+APCI MSm/z 192.1 [M+H-Boc]⁺.

Step B: (2S)-2-(benzyloxymethyl)pyrrolidine: To a solution of tert-butyl(2S)-2-(benzyloxymethyl)pyrrolidine-1-carboxylate (8.2 g, 28.14 mmol) inCH₂Cl₂ (28 mL) was added TFA (43.1 g, 378 mmol, 28.0 mL) dropwise at 0°C. under nitrogen atmosphere. The mixture was stirred at 15° C. for 1hour. The mixture was concentrated under vacuum. The residue was dilutedwith dichloromethane (100 mL) and then washed with 1M aqueous sodiumhydroxide (10 mL) until the aqueous layer reached pH˜10. The separatedorganic layer was washed with brine (2×20 mL), dried over sodiumsulfate, filtered and concentrated under vacuum to give(2S)-2-(benzyloxymethyl)pyrrolidine (4 g, 20.9 mmol, 74.3% yield LCMSES+APCI MS m/z 192.2 [M+H]⁺.

Step C: (2S)-2-(benzyloxymethyl)-1-(2-methoxyethyl)pyrrolidine: Amixture of 1-bromo-2-methoxy-ethane (0.9 g, 6.48 mmol, 608 uL),(2S)-2-(benzyloxymethyl)pyrrolidine (1.24 g, 6.48 mmol) and K₂CO₃ (2.68g, 19.4 mmol) in CH₃CN (20 mL) was stirred at 15° C. for 1 hours andthen at 78° C. for 12 hours. The mixture was diluted with ethyl acetate(50 mL) and water (50 mL). The separated organic layer was washed withbrine (1×50 mL), dried over sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by column chromatography oversilica gel (ethyl acetate/dichloromethane/methanol 1/1/0 to 10/10/2) togive (2S)-2-(benzyloxymethyl)-1-(2-methoxyethyl)pyrrolidine (900 mg,3.61 mmol, 55.7% yield) as a colorless oil. ES+APCI MS m/z 250.2 [M+H]⁺.

Step D: (S)-(1-(2-methoxyhexyl)pyrrolidin-2-yl)methanol: A solution of(2S)-2-(benzyloxymethyl)-1-(2-methoxyethyl)pyrrolidine (900 mg, 3.61mmol) in MeOH (20 mL) was added 10% Pd/C (721.88 umol) and the slurrystirred under H₂ (50 psi) at 10° C. for 16 hours. The reaction wasfiltered and the filtrate concentrated under vacuum to give(S)-(1-(2-methoxyethyl)pyrrolidin-2-yl)methanol (450 mg, 2.83 mmol,78.30% yield).

Step E: Benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:A mixture of [(2S)-1-(2-methoxyethyl)pyrolidin-2-yl]methanol (245 mg,1.54 mmol), benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 772 umol), and t-BuONa (223 mg, 2.32 mmol) in THF (5 mL) wasstirred at 20° C. for 0.5 hour under N₂ atmosphere. The reaction mixturewas poured into H₂O (30 mL) and the aqueous layer extracted with ethylacetate (3×30 mL). The combined organics were washed with brine (30 mL),dried over anhydrous Na₂SO₄ and concentrated under vacuum to give aresidue. The residue was purified by column chromatography (SiO₂,DCM/MeOH=300/1 to 10:1) to give Benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(260 mg, 349 umol, 45.3% yield). ES+APCI MS m/z 743.4 [M+H]⁺.

Step F: tert-Butyl4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(240 mg, 323 umol) and (Boc)₂O (141 mg, 646 umol, 148 uL) in MeOH (150mL) was added 10% Pd/C (100 mg) under N₂ atmosphere. The suspension wasdegassed and purged with H₂ 3 times. The mixture was stirred under H₂(15 PSI) at 40° C. for 12 hours. The reaction mixture was filtered andthe filtrate concentrated to give tert-Butyl4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(215 mg, crude). ES+APCI MS m/z 619.1 [M+H]⁺.

Step G:4-[2-[[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol.To a solution of tert-butyl4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(215 mg, 347 umol) in DCM (500 uL) was added TFA (594 mg, 5.21 mmol, 385uL) and the mixture stirred at 15° C. for 1 hour. The mixture wasconcentrated under vacuum to give4-[2-[[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol(219 mg, 346 umol). ES+APCI MS m/z 519.4 [M+H]⁺.

Step H:1-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a mixture of 4-[2-[[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol(219 mg, 346 umol) and DIEA (447 mg, 3.46 mmol, 603 uL) indichloromethane (4.00 mL) cooled to −40° C. was added a solution ofprop-2-enoyl prop-2-enoate (34.9 mg, 276.92 umol) in dichloromethane(1.00 mL) under a nitrogen atmosphere. The mixture was stirred at −40°C. for 1 hour. The reaction was quenched by addition of saturated NaHCO₃(2.00 mL) and the mixture poured into ice-water (20 mL) and extractedwith dichloromethane (20 mL×2). The combined organics were dried oversodium sulfate, filtered and concentrated in vacuo. The residue waspurified by prep-HPLC (column: Gemini 150*25 5 u; mobile phase: [water(0.05% ammonia hydroxide v/v)-ACN]; B %: 32%-62%, 12 min) to give1-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(27 mg, 46.7 umol). ES+APCI MS m/z 573.3 [M+H]⁺.

Example 1451-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: Benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(2S)-1-tert-butoxycarbonylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of tert-butyl (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.24 g, 6.17 mmol) and benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(2 g, 3.09 mmol) in THF (50 mL) was added t-BuONa (890 mg, 9.26 mmol)and the reaction stirred at 15° C. for 0.5 hour. The reaction mixturewas poured into H₂O (100 mL) and extracted with ethyl acetate (3×100mL). The combined organics were washed with brine (50 mL), dried overanhydrous Na₂SO₄ and concentrated under vacuum to give a residue. Theresidue was purified by column chromatography (SiO2, Petroleumether/Ethyl acetate=100/1 to 1:1) to give Benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(2S)-1-tert-butoxycarbonylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1.62 g, 2.02 mmol, 65.5% yield). ES+APCI MS m/z 785.6 [M+H]⁺.

Step B:(2S)-2-[[7-(3-hydroxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate:NH₃ was bubbled into MeOH (50 mL) at 15° C. for 30 minutes. To thissolution was added benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(2S)-1-tert-butoxycarbonylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1.6 g, 2.04 mmol) followed by dry 10% Pd/C (500 mg) under N₂. Thesuspension was degassed under vacuum and purged with H₂ several times.The mixture was stirred under H₂ (15 psi) at 40° C. for 1 hour. Themixture was then filtered and the filtrate concentrated under vacuum togive tert-butyl(2S)-2-[[7-(3-hydroxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate(1.00 g, 1.78 mmol). ES+APCI MS m/z 561.5 [M+H]⁺.

Step C: tert-butyl(2S)-2-[[7-(3-hydroxy-1-naphthyl)-4-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate:To a solution of tert-butyl(2S)-2-[[7-(3-hydroxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate(800 mg, 1.43 mmol) in DCM (5.00 mL) at at 0° C. was added TFAA (599 mg,2.85 mmol) and DIEA (737 mg, 5.71 mmol) and the reaction stirred at 0°C. for 0.5 hour. The reaction mixture was poured into H₂O (50 mL) andextracted with ethyl acetate (50 mL×3). The combined organics werewashed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum to give tert-butyl(2S)-2-[[7-(3-hydroxy-1-naphthyl)-4-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate(1.5 g, crude). ES+APCI MS m/z 657.5 [M+H]⁺.

Step D:2,2,2-trifluoro-1-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]ethanone:To a solution of tert-butyl(2S)-2-[[7-(3-hydroxy-1-naphthyl)-4-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate(300 mg, crude) in DCM (500 uL) was added TFA (521 mg, 4.57 mmol, 338uL) and the mixture stirred at 15° C. for 1 hour. The mixture wasconcentrated under vacuum to give2,2,2-trifluoro-1-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]ethanone(306 mg). ES+APCI MS m/z 557.3 [M+H]⁺.

Step E:2,2,2-trifluoro-1-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]ethanone:To a solution of acetone (132 mg, 2.28 mmol, 167 uL,) and2,2,2-trifluoro-1-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]ethanone(306 mg, crude, TFA) in MeOH (5.00 mL) was added AcOH (54.8 mg, 912umol, 52.2 uL) and NaBH₃CN (115 mg, 1.83 mmol) and the mixture stirredat 15° C. for 16 hours. The reaction mixture was diluted with H₂O (20mL) and extracted with ethyl acetate (20 mL×3). The combined organicswere washed with brine (10 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give2,2,2-trifluoro-1-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]ethanone(300 mg, crude). ES+APCI MS m/z 599.5 [M+H]⁺.

Step F:4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol:To a solution of2,2,2-trifluoro-1-[4-[7-(3-hydroxy-1-naphthyl-2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]ethanone(300 mg, crude) in MeOH (10 mL) was added K₂CO₃ (346 mg, 2.51 mmol) andthe mixture stirred at 15° C. for 1 hour. The reaction mixture wasfiltered and the filtrate concentrated to give4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol(250 mg). ES+APCI MS m/z 503.3 [M+H]⁺.

Step G:1-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a mixture of4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol(250 mg, crude) and DIEA (643 mg, 4.97 mmol, 866 uL) in DCM (5.00 mL)cooled to −40° C. was added a solution of prop-2-enoyl prop-2-enoate(50.2 mg, 398 umol) in DCM (1 mL) under nitrogen atmosphere. The mixturewas stirred at −40° C. for 1 hour. The reaction was quenched by additionof saturated NaHCO₃ (2.00 mL). The mixture was poured into ice-water (20mL) and extracted with DCM (20 mL×2). The combined organics were driedover sodium sulfate, filtered and concentrated in vacuo. The residue waspurified by prep-HPLC (column: Phenomenex Gemini 150*25 mm*10 um; mobilephase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 52%-78%, 12 min),1-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(10 mg, 17.6 umol). ES+APCI MS m/z 557.3 [M+H]⁺.

Example 1461-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(3R)-pyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:A mixture of benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.50 g, 772 umol), tert-butyl(3R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (311 mg, 1.54 mmol) andt-BuONa (223 mg, 2.32 mmol) in THF (10 mL) was stirred at 20° C. for 1hour. The mixture was diluted with water (10 mL) and the aqueous layerextracted with ether acetate (3 r 20 mL) The combined organics werewashed with saturated sodium chloride (1×30 mL), dried over Na₂SO₄,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography (SiO₂, petroleum ether/ether acetate=3/1) to givebenzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.40 g, 499 umol). ES+APCI MS m/z 785.2 [M+H]⁺.

Step B: tert-butyl(3R)-3-[[7-(3-hydroxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate: NH₃ was bubbled intomethanol (10 mL) at −78° C. for 30 minutes. Benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.25 g, 319 umol) and 10% Pd/C (0.10 g) were added into the mixture andstirred at 10° C. for 1 hour under H₂ (15 psi). The mixture was filteredand concentrated under vacuum to give tert-butyl(3R)-3-[[7-(3-hydroxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate (0.17 g, 303 umol).ES+APCI MS m/z 561.3 [M+H]⁺.

Step C: tert-butyl(3R)-3-[[7-(3-hydroxy-1-naphthyl)-4-(4-prop-2-enoylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate:To a solution of tert-butyl(3R)-3-[[7-(3-hydroxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate(0.17 g, 303 umol) and Et₃N (153 mg, 1.52 mmol, 211 uL) indichloromethane (4.00 mL) cooled to −40° C. was added prop-2-enoylprop-2-enoate (26.8 mg, 212 umol) and the mixture stirred at −40° C. for0.5 h. The mixture was quenched by addition of methanol (0.10 mL) andconcentrated under vacuum. The residue was purified by columnchromatography (Al₂O₃, dichloromethane/methane=10/1) to give tert-butyl(3R)-3-[[7-(3-hydroxy-1-naphthyl)-4-(4-prop-2-enoylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate(0.12 g, 189 umol). ES+APCI MS m/z 615.5 [M+H]⁺.

Step D:1-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(3R)-pyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:A mixture of tert-butyl(3R)-3-[[7-(3-hydroxy-1-naphthyl)-4-(4-prop-2-enoylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate(0.10 g, 163 umol) and TFA (278 mg, 2.44 mmol, 181 uL) indichloromethane (0.20 mL) was stirred at 10° C. for 1 hour. The mixturewas quenched by addition of NH₃·H₂O and the pH adjusted until the pH=7.The mixture was purified by prep-HPLC (column: Venusil XBP C8 150*25*10um, mobile phase: [water (0.225% Formic Acid)-ACN]; B %: 15%-45%, 10min) to give1-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(3R)-pyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(22.8 mg, 42.9 umol). ES+APCI MS m/z 515.4 [M+H]⁺.

Example 1472-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: (Z) and (E)-4-bromobut-2-enenitrile: To a solution ofbut-3-enenitrile (98 g, 1.46 mol, 118 mL) in tert-butanol (150 mL) andpetroleum ether (575 mL) was added a solution of Br₂ (233 g, 1.46 mol,75.3 mL) in tert-butanol (150 mL) at 15° C. and the reaction stirred for30 minutes. To the reaction was next added an ethanol solution of sodiumethoxide (100 g, 0.6 mol, 850 mL). The reaction mixture was stirred for2 hours at the 15° C. The reaction was next filtered and the filtrateconcentrated under vacuum. The residue was purified by columnchromatography using 2→20% ethyl acetate/petroleum ether as eluent togive a mixture of (Z) and (E)-4-bromobut-2-enenitrile (141 g, E/Z=2.5/1,crude) as a slight yellow oil. ¹H NMR (400 MHz, chloroform-d,) (E), δ6.79 (td, J=7.2, 16.0 Hz, 1H), 5.63 (d, J=16.0 Hz, 1H), 4.00 (dd, J=1.2,6.8 Hz, 2H); (Z), δ=6.66 (td, J=8.0, 10.8 Hz, 1H), 5.44 (d, J=10.8 Hz,1H), 4.16 (dd, J=0.8, 8.0 Hz, 2H).

Step B: 2-(1,4-dibenzylpiperazin-2-yl)acetonitrile: To a mixture ofN,N′-dibenzylethane-1,2-diamine (115 g, 480 mmol, 113 mL) and TEA (97.0g, 959 mmol, 133 mL) in toluene (1 L) was added 4-bromobut-2-enenitrile(70 g, crude) dropwise at 0° C. and the reaction stirred at 15° C. for12 hours. The reaction mixture was filtered and the filtrateconcentrated under reduced pressure. The residue was purified by columnchromatography using 5→50% EtOAc/Petroleum Ether as eluent to give2-(1,4-dibenzylpiperazin-2-yl)acetonitrile (82 g, 240 mmol, two steps37% yield, 89.3% purity) as a slight yellow semisolid. ES+APCI MS m/z306.3 [M+H]⁺. ¹H NMR (400 MHz, chloroform-d) δ=7.40-7.23 (m, 10H),3.85-3.76 (m, 1H), 3.54-3.44 (m, 3H), 3.07-2.96 (m, 1H), 2.94-2.84 (m,1H), 2.68-2.35 (m, 7H).

Step C: 2-piperazin-2-ylacetonitrile: To a solution of2-(1,4-dibenzylpiperazin-2-yl)acetonitrile (164 g, 536 mmol) in DCE(1500 mL) was added 1-chloroethyl carbonochloridate (306 g, 2.14 mol)dropwise at 0° C. After addition, the reaction mixture was heated to 85°C. for approximately 48 hours. The dichloroethane was evaporated and theresidue was taken up in MeOH (1500 mL) and heated to 70° C. for 1 hour.The reaction mixture was concentrated under reduced pressure and thesolids triturated with MTBE (3×3 L) and the solids dried under reducedpressure to give 2-piperazin-2-ylacetonitrile. The crude product waspurified by recrystallization with Ethanol and water (8:1, v:v) to give2-piperazin-2-ylacetonitrile as an off-white solid (53 g, 428 mmol,40.0% yield, 96.4% purity, 2 HCl). ES+APCI MS m/z 126.2 [M+H]⁺. ¹H NMR(400 MHz, D₂O) δ=4.01-3.96 (m, 1H), 3.81-3.67 (m, 3H), 3.46-3.27 (m,3H), 3.09 (d, J=6.0 HZ, 2H).

Step D:2-[4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl]acetonitrile:To a mixture of7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (1.2 g,4.08 mmol) and 2-piperazin-2-ylacetonitrile (808 mg, 4.08 mmol, 2HCl) indioxane (24 mL) was added DIEA (2.64 g, 20.4 mmol, 3.55 mL). Thereaction mixture was stirred at 50° C. for 3 hours. Upon completion, thereaction mixture was diluted with water (50 mL) and the aqueous layerextracted with EtOAc (3×80 mL). The combined organic layers were washedwith brine (30 mL), dried over Na₂SO₄ and concentrated under vacuum togive2-[4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl]acetonitrile(1.56 g, 4.07 mmol, 100% yield) as a brown solid.

Step E: tert-butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:To2-[4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl]acetonitrile(1.56 g, 4.07 mmol) was added (Boc)₂O (9.50 g, 43.5 mmol, 10 mL) and themixture heated to 50° C. for 2 hours. Upon completion, the reactionmixture was purified by silica gel chromatography using 10→50%EtOAc/Petroleum Ether as eluent to give tert-butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(1.2 g, 2.44 mmol, 59.9% yield, 98.3% purity) as brown solid. ES+APCI MSm/z 483.3 [M+H]⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.39-7.27 (m, 5H),4.59 (br s, 1H), 4.06 (br d, J=13.6 Hz, 2H), 3.90 (br d, J=11.6 Hz, 1H),3.74-3.49 (m, 4H), 3.29 (dd, J=4.0, 13.6 Hz, 1H), 3.18 (br s, 1H),3.10-3.00 (m, 1H), 2.85-2.55 (m, 6H), 1.53-1.45 (m, 9H).

Step F: tert-butyl4-[7-benzyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate:To a solution of [(2S)-1-methylpyrrolidin-2-yl]methanol (655.74 mg, 5.69mmol, 676 uL in THF (25 mL) was added NaH (182 mg, 4.55 mmol, 60%purity) at 0° C. and the reaction mixture stirred at 0° C. for 0.5 h. Tothe mixture was added tert-butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (1.1 g, 2.28 mmol) and the reaction mixturestirred at 70° C. for 12 hours in a sealed tube under N₂. Uponcompletion, the reaction mixture was quenched by addition of saturatedNH₄Cl (20 mL) and the aqueous layer extracted with EtOAc (2×50 mL). Thecombined organics were washed with brine (10 mL), dried over Na₂SO₄,filtered and concentrated under vacuum to give tert-butyl4-[7-benzyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(1.1 g, 1.86 mmol, 81.7% yield, 95% purity) as a brown solid. ES+APCI MSm/z 562.4 [M+H]⁺.

Step G: tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:Ammonia was bubbled into MeOH (30 mL) for 5 minutes. To this solutionwas added tert-butyl4-[7-benzyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(950 mg, 1.69 mmol) and 10% Pd/C (200 mg). The suspension was degassedunder vacuum and purged with H₂ several times and the mixture stirredunder H₂ (15 psi) at 40° C. for 9 hours. Upon completion, the reactionmixture was filtered and concentrated under vacuum. The residue waspurified by prep-HPLC (column: Phenomenex Synergi Max-RP 250*50 mm*10um; mobile phase: [water (0.225% Formic Acid)-ACN]; B %: 15%-40%, 30;58% min) to give tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(400 mg, 830 umol, 49.1% yield, 97.8% purity) was obtained as brown oil.ES+APCI MS m/z 472.4 [M+H]⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ=4.59 (brs, 1H), 4.43-4.28 (m, 1H), 4.18-4.09 (m, 1H), 4.07-3.90 (m, 4H),3.88-3.78 (m, 1H), 3.21 (br dd, J=3.2, 13.6 Hz, 2H), 3.16-3.05 (m, 2H),3.03-2.90 (m, 2H), 2.82-2.55 (m, 4H), 2.48 (s, 3H), 2.33-2.22 (m, 1H),2.11-2.00 (m, 1H), 1.91-1.62 (m, 4H), 1.51 (s, 9H).

Step H: tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(150 mg, 318 umol), 1-bromonaphthalene (98.8 mg, 477 umol, 66.3 uL),Cs₂CO₃ (311 mg, 954 umol), and RuPhos (29.7 mg, 63.6 umol) in toluene (3mL) was added Pd₂(dba)₃ (29.1 mg, 31.8 umol) and the suspension wasdegassed under vacuum and purged with N₂ 3 times. The reaction mixturewas stirred at 100° C. for 12 hours. The mixture was partitioned betweenwater (10 mL) and EtOAc (20 mL) and the layers separated. The aqueouslayer was extracted subsequently with EtOAc (3×20 mL). The combinedorganics were washed with brine (20 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by reverse flash to give tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(70 mg, 111 umol, 35.0% yield, 95.0% purity) as brown solid. ES+APCI MSm/z 598.6 [M+H]⁺. ¹H NMR (400 MHz, chloroform-d) δ=8.21-8.20 (m, 1H),7.87-7.85 (m, 1H), 7.61-7.59 (d, J=8.0 Hz, 1H), 7.51-7.49 (m, 2H),7.45-7.41 (t, J=7.6 Hz, 1H), 7.15-7.13 (d, J=7.2 Hz, 1H), 4.63 (br s,1H), 4.46 (br s, 1H), 4.33-4.28 (m, 4H), 4.10-4.07 (m, 2H), 3.97-3.94(br d, J=11.6 Hz, 1H), 3.46 (br s, 1H), 3.31-3.27 (br d, J=14.0 Hz, 1H),3.07-3.01 (m, 2H), 2.77 (br s, 3H), 2.55 (br s, 3H), 2.35 (br s, 1H),1.82 (br s, 7H), 1.52 (s, 9H).

Step I:2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile:To a solution of tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(60 mg, 100 umol) in DCM (0.1 mL) was added TFA (154 mg, 1.35 mmol, 0.1mL) at 15° C. and stirred at 15° C. for 1 hour. The reaction mixture wasconcentrated under vacuum to give2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(50 mg) as brown oil.

Step J:2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile:To a solution of2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(50 mg, 81.8 umol, TFA) and DIEA (106 mg, 817 umol, 142 uL) in DCM (0.2mL) was added prop-2-enoyl prop-2-enoate (11.3 mg, 89.9 umol) at 0° C.and the reaction stirred at 0-15° C. for 1.5 hour. The reaction mixturewas concentrated under vacuum. The residue was purified by prep-HPLC(column: Phenomenex Synergi C18 150*30 mm*4 um; mobile phase: [water(0.225% Formic Acid)-ACN]; B %: 15%-45%, 10.5 min) to give2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(9.16 mg, 15.1 umol, 18.5% yield, 98.7% purity, Formate) as yellow oil.ES+APCI MS m/z 552.5 [M+H]⁺. ¹H NMR (400 MHz, chloroform-d) δ=8.45 (brs, 1H), 8.22-8.19 (m, 1H), 7.87-7.85 (m, 1H), 7.62-7.60 (d, J=8.0 Hz,1H), 7.51-7.49 (m, 2H), 7.45-7.43 (t, J=7.6 Hz, 1H), 7.15-7.13 (d, J=7.2Hz, 1H), 6.60 (br s, 1H), 6.42-6.38 (m, 1H), 5.84-5.82 (br d, J=10.8 Hz,1H), 5.08 (br s, 1H), 4.78-4.53 (br dd, J=6.8, 11.6 Hz, 2H), 4.42-4.40(m, 1H), 4.27 (br s, 2H), 4.21-4.18 (br d, J=14.01 Hz, 1H), 4.12-3.78(br d, J=12.8 Hz, 2H), 3.68-3.07 (m, 7H), 3.05-2.84 (m, 3H), 2.77 (d,J=1.6 Hz, 3H), 2.71-2.64 (m, 1H), 2.26-2.17 (m, 1H), 2.11-2.03 (m, 1H),2.02-1.88 (m, 2H).

Example 1482-[4-[7-(5-methyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 424 umol), 4-bromo-5-methyl-1-tetrahydropyran-2-yl-indazole(188 mg, 636 umol), RuPhos (39.6 mg, 84.8 umol) and Cs₂CO₃ (414 mg, 1.27mmol) in toluene (6 mL) was added Pd₂(dba)₃ (38.8 mg, 42.4 umol) and thereaction stirred at 100° C. for 12 hours under N₂. Upon completion, themixture was purified directly by silica gel chromatography (PE:EtOAc=3:1to 0:1) to give tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(120 mg, 149 umol, 35.1% yield, 85.0% purity) as a brown solid. ES+APCIMS m/z 686.6 [M+H]⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.04 (d, J=2.0 Hz,1H), 7.33-7.29 (m, 2H), 5.70 (dd, J=2.4, 9.2 Hz, 1H), 4.62 (br s, 1H),4.39 (br s, 1H), 4.34-4.28 (m, 2H), 4.20-4.14 (m, 1H), 4.05 (br d,J=12.0 Hz, 2H), 3.91 (br d, J=12.4 Hz, 1H), 3.81-3.72 (m, 1H), 3.53 (brt, J=4.8 Hz, 2H), 3.27 (br d, J=10.8 Hz, 2H), 3.10 (br d, J=6.8 Hz, 1H),3.06-2.96 (m, 1H), 2.90-2.65 (m, 5H), 2.59 (br d, J=10.2 Hz, 1H), 2.50(s, 3H), 2.43 (s, 3H), 2.35-2.26 (m, 1H), 2.23-2.15 (m, 1H), 2.11 (br s,2H), 1.90-1.65 (m, 7H), 1.54 (s, 9H).

Step B:2-[4-[7-(5-methyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile:To a solution of tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(150 mg, 219 umol) in DCM (0.2 mL) was added TFA (616 mg, 5.40 mmol, 0.4mL) and the reaction mixture stirred at 15° C. for 12 hours. Uponcompletion, the solvent was removed under vacuum to give2-[4-[7-(5-methyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(159 mg, 218 umol, 99.6% yield, 2 TFA) as a red oil.

Step C:2-[4-[7-(5-methyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile:To a solution of2-[4-[7-(5-methyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(159 mg, 218 umol, 2 TFA) and DIEA (366 mg, 2.83 mmol, 493 uL) in DCM (4mL) at −40° C. was added prop-2-enoyl prop-2-enoate (24.7 mg, 196 umol,)and the reaction mixture was stirred at −20° C. for 1 hour. Uponcompletion, the reaction mixture was quenched by addition of water (2mL) and the aqueous layer separated and back extracted with DCM (2×10mL) The combined organics were concentrated under vacuum and the residuepurified by silica gel chromatography (DCM:MeOH=50:1 to 5:1) followed bypurification by reverse prep HPCL (column: Phenomenex Synergi C18150*25*10 um; mobile phase: [water (0.225% Formic Acid)-ACN]; B %:4%-34% over 10 minutes) to give2-[4-[7-(5-methyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(1.77 mg, 3.10 umol). ES+APCI MS m/z 556.5 [M+H]⁺. ¹H NMR (400 MHz,CHLOROFORM-d) δ=8.00 (s, 1H), 7.18 (br s, 1H), 7.16-7.11 (m, 1H), 6.52(br s, 1H), 6.37-6.21 (m, 1H), 5.75 (br d, J=10.4 Hz, 1H), 4.99 (br s,1H), 4.67 (br dd, J=6.4, 11.6 Hz, 1H), 4.34 (br dd, J=3.9, 11.6 Hz, 1H),4.24 (s, 2H), 4.11 (br d, J=12.8 Hz, 1H), 3.94 (br s, 1H), 3.57-3.40 (m,4H), 3.29 (br d, J=13.8 Hz, 1H), 3.19 (br s, 1H), 3.02 (br dd, J=12.4,19.7 Hz, 2H), 2.87 (br dd, J=8.4, 16.4 Hz, 2H), 2.76-2.58 (m, 6H), 2.35(s, 3H), 2.22-2.10 (m, 1H), 2.01 (br d, J=8.4 Hz, 1H), 1.89 (br s, 2H).

Example 1492-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1H-indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: tert-butyl 2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:tert-butyl 2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(130 mg, 276 umol),2-[[4-bromo-5-(trifluoromethyl)indazol-1-yl]methoxy]ethyl-trimethyl-silane(120 mg, 303 umol), Pd(dba); (50.5 mg, 55.1 umol), RuPhos (51.5 mg, 110umol), Cs₂CO₃ (225 mg, 689 umol) in toluene (3.00 mL) was de-gassed withN₂ and then heated to 90° C. for 12 hours under N₂. Upon completion, themixture was filtered and the filtrate was concentrated. The residue waspurified by prep-TLC (EtOAc/MeOH 8/1) to give tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(140 mg, 169 umol, 61.4% yield, 95.0% purity) as a yellow solid. ES+APCIMS m/z 786.3 [M+H]⁺.

Step B: 2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile:To a solution of tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(140 mg, 178 umol) in DCM (3.00 mL) was added 2,6-dimethylpyridine (229mg, 2.14 mmol) and TMSOTf (238 mg, 1.07 mmol) at 0° C. The mixture wasstirred at 15° C. for 2 hours. Upon completion, the mixture was quenchedby addition of MeOH (0.5 mL) and concentrated under vacuum to give2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(200 mg, crude) as a yellow oil which was used directly in the next stepwithout further purification. ES+APCI MS m/z 686.6 [M+H]⁺.

Step C:2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile:To a solution of2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(122 mg, 178 umol) and DIEA (138 mg, 1.07 mmol, 186 uL) in DCM (3.00 mL)was added prop-2-enoyl prop-2-enoate (18.0 mg, 143 umol) dropwise at 0°C. The mixture was stirred at 20° C. for 1.5 hours. Upon completion, themixture was diluted with water (0.5 mL) and extracted with EtOAc (2×5mL). The organic layers were dried over Na₂SO₄ and concentrated undervacuum. The residue was purified by prep-TLC (EA/MeOH 10/1) andprep-HPLC (column: Boston pH-lex 150*25 10 um; mobile phase: [water(0.1% TFA)-ACN]; B %: 39%-69%, 10 min) to give2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(54.0 mg, 43.8 umol). ES+APCI MS m/z 740.6 [M+H]⁺.

Step D:2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1H-indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile:To a solution of2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(20 mg, 27.0 umol) in DCM (60 uL) was added TFA (30.8 mg, 270 umol) Themixture was stirred at 20° C. for 1 hour. The reaction was not completeso additional TFA (30.8 mg) was added and the reaction stirred at 20° C.for an additional 0.5 hour. Upon completion, the pH or the mixture wasadjusted to 8 by addition of saturated aqueous NaHCO₃ (1 mL) and theaqueous layer extracted with EtOAc (2-5 mL). The combined organics werewashed with brine (3 mL), dried over Na₂SO₄ and concentrated undervacuum. The residue was diluted with MeOH (0.5 mL) and NH₃·H₂O (0.5 mL)added and the mixture stirred at 20° C. for 0.5 hour. The mixture waspurified by prep-HPLC (column: Phenomenex Synergi C18 150*30 mm*4 um;mobile phase: [water (0.225% Formic Acid)-ACN]; B %: 15%-45%, 10.5 min)to give2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1H-indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(2.68 mg, 3.99 umol) as a white solid. ES+APCI MS m/z 610.5 [M+H]⁺. ¹HNMR (400 MHz, chloroform-d) δ=8.22 (s, 1H), 7.68 (d, J=9.2 Hz, 1H), 7.45(d, J=8.8 Hz, 1H), 6.60 (br s, 1H), 6.45-6.35 (m, 1H), 5.84 (br d,J=11.2 Hz, 1H), 5.09 (br s, 1H), 4.71-4.60 (m, 1H), 4.42-4.27 (m, 3H),4.17 (br d, J=11.2 Hz, 1H), 4.01 (br d, J=12.4 Hz, 2H), 3.78-3.31 (m,5H), 3.23-3.03 (m, 2H), 3.02-2.75 (m, 4H), 2.71 (s, 3H), 2.66-2.57 (m,1H), 2.27-2.12 (m, 1H), 2.10-2.03 (m, 3H) ES+APCI MS m/z 610.1 [M+H]⁺.

Example 1502-(1-acryloyl-4-(2-(((R)-1-(dimethylamino)propan-2-yl)oxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: tert-Butyl4-[7-benzyl-2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate:To a mixture of tert-butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(500 mg, 1.04 mmol), (2R)-1-(dimethylamino)propan-2-ol (214 mg, 2.07mmol and sodium tert-butoxide (298 mg, 3.11 mmol) in toluene (20 mL) wasadded BINAP (129 mg, 207 umol) and Pd₂(dba)₃ (94.8 mg, 104 umol) and themixture was sparged with nitrogen followed by stirring at 90° C. for 5hr. The mixture was diluted with ethyl acetate (100 mL) and water (100mL) and the organic layer was separated and dried over sodium sulfate,filtered and concentrated under vacuum. The residue was purified byreversed phase flash chromatogaphy [water (0.1% Formic Acidwater)/acetonitrile]. The desired fractions were collected andneutralized with saturated aqueous sodium carbonate solution (5 mL) andextracted with 10% MeOH/DCM (2×50 mL). The combined organics were driedover sodium sulfate, filtered and concentrated under vacuum to givetert-Butyl4-[7-benzyl-2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(300 mg, 480 umol) ES+APCI MS m/z 550.4 [M+H]⁺.

Step B: tert-butyl2-(cyanomethyl)-4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of tert-butyl4-[7-benzyl-2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(1.1 g, 2.00 mmol) in MeOH (10 mL) was added a solution of NH₃ (792 mg,46.5 mmol) in MeOH (3.96 g, 123.56 mmol, 5 mL), followed by 10% Pd/C(500 mg). The mixture was stirred at 40° C. for 12 hr under H₂ (15 psi).The reaction was filtered and the filtrate was concentrated underreduced pressure to dryness to give tert-butyl2-(cyanomethyl)-4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(756 mg, crude) was obtained as a yellow solid. ES+APCI MS m/z 460.3[M+H]⁺.

Step C: tert-butyl2-(cyanomethyl)-4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:A mixture of (4-bromo-2-naphthyl) 2,2-dimethylpropanoate (304 mg, 990umol), tert-butyl2-(cyanomethyl)-4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(350 mg, 761 umol), [2-(2-aminoethyl)phenyl]-chloro-palladium,dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (84.4 mg, 114umol) and Cs₂CO₃ (620 mg, 1.90 mmol in toluene (10 mL) was purged withN₂ 3 times and the mixture stirred at 70° C. for 16 hours under N₂atmosphere. The reaction mixture was poured into H₂O (50 mL) andextracted with ethyl acetate (50 mL×3). The combined organics werewashed with brine (30 mL), dried over anhydrous Na₂SO₄ and concentratedunder vacuum to give a residue. The residue was purified by reversedphase flash [water (0.1% formic acid)/acetonitrile] to give tert-butyl2-(cyanomethyl)-4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(210 mg, 303 umol). ES+APCI MS m/z 686.4 [M+H]⁺.

Step D:[4-[4-[3-(cyanomethyl)piperazin-1-yl]-2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate: To a solution of tert-butyl2-(cyanomethyl)-4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(210 mg, 306 umol) in dichloromethane (300 uL) was added TFA (523 mg,4.59 mmol, 340 uL) and the mixture stirred at 15° C. for 2 hours. Themixture was concentrated under vacuum to give[4-[4-[3-(cyanomethyl)piperazin-1-yl]-2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate(214 mg, 305 umol). ES-APCI MS m/z 586.4 [M+H]⁺.

Step E:[4-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate:To a mixture of[4-[4-[3-(cyanomethyl)piperazin-1-yl]-2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate(214 mg, 305 umol, TFA) and DIEA (395 mg, 3.06 mmol, 532 uL) indichloromethane (5.00 mL) cooled to −40° C. was added a solution ofprop-2-enoyl prop-2-enoate (38.6 mg, 305 umol) in dichloromethane (1.00mL) under nitrogen atmosphere. The mixture was warmed up to 0° C. andstirred for 1 hour. The mixture was concentrated under vacuum to give aresidue. The residue was purified by reversed phase flash [water (0.1%trifluoroacetic acid)\acetonitrile] to give[4-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[(1R)-2-(dimethylamino)-1-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (100 mg, 156 umol). ES+APCI MS m/z 640.7 [M+H]⁺.

Step F:2-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile:To a solution of[4-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (90 mg, 141 umol) in THF (500 uL) cooled to 0° C.was added NaOH (2 M, 281.34 uL) and the mixture stirred at 15° C. for 16hours. The pH of the mixture was adjusted to 7 by addition of a 20% withformic acid solution. The aqueous solution was next extracted withdichloromethane (3×10 mL). The combined organics were dried over Na₂SO₄,filtered and concentrated under vacuum. The residue was purified byprep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase:[water (0.225% Formic Acid)-ACN]; B %: 7%-37%, 10 min) to give2-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(5 mg, 8.82 umol, 6.27% yield, 98% purity) ES+APCI MS m/z 556.3 [M+H]⁺.¹H NMR (400 MHz, methanol-d₄) δ=8.54 (br s, 0.6H), 8.07 (d, J=8.4 Hz,1H), 7.63 (d, J=8.4 Hz, 1H), 7.37 (t, J=7.2 Hz, 1H), 7.30-7.21 (m, 1H),6.91-6.72 (m, 3H), 6.29 (br d, J=16.4 Hz, 1H), 5.84 (br d, J=11.2 Hz,1H), 5.48 (br s, 1H), 5.26-4.96 (m, 1H), 4.57 (br s, 1H), 4.24-4.09 (m,4H), 3.74-3.54 (m, 1H), 3.48 (m, 2H), 3.22 (m, 2H), 3.10-2.86 (m, 5H),2.78 (br d, J=14.4 Hz, 1H), 2.53 (br s, 6H), 1.37 (dd, J=2.0, 6.4 Hz,3H).

Example 1512-(1-acryloyl-4-(2-(((R)-1-(dimethylamino)propan-2-yl)oxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

(2-(1-acryloyl-4-(2-(((R)-1-(dimethylamino)propan-2-yl)oxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrilewas prepared following Example 150 substituting 1-bromonaphthalene for(4-bromo-2-naphthyl) 2,2-dimethylpropanoate in Step C and omitting StepF. ES+APCI MS m/z 540.3 [M+H]⁺. ¹H NMR (400 MHz, methanol-d₄) δ=8.51 (s,1H), 8.26-8.19 (m, 1H), 7.90-7.84 (m, 1H), 7.62 (d, J=8.0 Hz, 1H),7.53-7.47 (m, 2H), 7.46-7.39 (m, 1H), 7.25-7.18 (m, 1H), 6.82 (br s,1H), 6.30 (br d, J=17.2 Hz, 1H), 5.84 (br d, J=10.4 Hz, 1H), 5.62-5.53(m, 1H), 5.08 (br s, 1H), 4.70-4.39 (m, 1H), 4.26-4.11 (m, 4H),3.94-3.59 (m, 1H), 3.48-3.34 (m, 2H), 3.28-3.18 (m, 3H), 3.13-2.92 (s,5H), 2.79-2.61 (s, 6H), 1.48 (dd, J=2.0, 6.0 Hz, 3H).

Example 1522-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1H-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: tert-butyl2-(cyanomethyl)-4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:A mixture of tert-butyl2-(cyanomethyl)-4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.50 g, 1.09 mmol), 4-bromo-5-methyl-1-tetrahydropyran-2-yl-indazole(482 mg, 1.63 mmol), t-BuONa (314 mg, 3.26 mmol) and[2-(2-aminoethyl)phenyl]-chloro-palladium;dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (80.4 mg, 109umol) in toluene (30 mL) was stirred at 70° C. for 10 hours. The mixturewas diluted with water (10 mL) and the aqueous layer extracted withethyl acetate (3×20 mL). The organic layers were washed with saturatedsodium chloride solution (30 mL), dried over Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by reverse phaseflash [water (Formic Acid, 0.1%.)/acetonitrile] to give tert-butyl2-(cyanomethyl)-4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.40 g, 522 umol, 48.0% yield) as a yellow solid. ES+APCI MS m/z 674.3[M+H]⁺. ¹H NMR (400 MHz, chloroform-d) δ 8.03 (d, J=1.6 Hz, 1H),7.31-7.27 (m, 2H), 5.68 (dd, J=2.4, 9.6 Hz, 1H), 5.31 (br s, 1H), 4.61(br s, 1H), 4.28 (s, 2H), 4.08-3.94 (m, 3H), 3.86 (br d, J=11.6 Hz, 1H),3.79-3.71 (m, 1H), 3.52 (br t, J=4.8 Hz, 2H), 3.24 (br d, J=12.8 Hz,2H), 3.04-2.91 (m, 1H), 2.87-2.67 (m, 5H), 2.65-2.47 (m, 2H), 2.41 (s,3H), 2.32 (br s, 6H), 2.17 (br d, J=4.0 Hz, 1H), 2.09 (br s, 1H), 1.77(br t, J=10.8 Hz, 3H), 1.52 (s, 9H), 1.36 (d, J=6.0 Hz, 3H).

Step B:2-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile:To a solution of tert-butyl2-(cyanomethyl)-4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.38 g, 564 umol) in dichloromethane (10 mL) was added TMSOTf (752 mg,3.38 mmol) and 2,6-dimethylpyridine (725 mg, 6.77 mmol) at 0° C. and themixture stirred at 10° C. for 1 hour. The mixture was quenched byaddition of methanol (0.10 mL) and concentrated under vacuum. Theresidue was purified by reversed phase chromatography [water (FormicAcid, 0.1%)acetonitrile]. The collected fractions were combined and thepH adjusted pH>7 by addition of saturated sodium bicarbonate solutionand the aqueous layer extracted with dichloromethane/methanol (10/1)(3×10 mL). The extracts were washed with saturated sodium chloridesolution (10 mL), dried over Na₂SO₄, filtered and concentrated undervacuum to give2-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(0.30 g, crude) as a yellow solid. ES+APCI MS m/z 574.1 [M+H]⁺.

Step C:2-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile:To a solution of2-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(0.20 g, crude) and TEA (176 mg, 1.74 mmol, 243 uL) in dichloromethane(1.00 mL) was added prop-2-enoyl prop-2-enoate (44.0 mg, 349 umol) at 0°C. and the reaction stirred at 0° C. for 0.5 h. The mixture was quenchedby addition of methanol (0.10 mL) and concentrated under vacuum. Theresidue was purified by reversed phase flash [water (Formic Acid,0.1%)/acetonitrile]. The collected fractions were combined and the pHadjusted to pH>7 by addition of saturated sodium bicarbonate solutionand the aqueous layer extracted with dichloromethane/methanol (10/1)(3×5.00 mL). The extracts were washed with saturated sodium chloridesolution (1×10 mL), dried over Na₂SO₄, filtered and concentrated undervacuum to give2-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(0.10 g, 127 umol, two steps 36.6% yield) as a yellow solid. ES+APCI MSm/z 628.6 [M+H]⁺.

Step D:2-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1H-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile:A mixture of2-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(40 mg, 63.7 umol,) and TsOH (1.10 mg, 6.37 umol) in acetonitrile (3 mL)was stirred at 90° C. for 1 hour. The mixture was quenched by additionof saturated sodium bicarbonate (2 mL) at 0° C. and concentrated undervacuum. The residue was purified by column chromatography (Al₂O₃,dichloromethane/methanol 5/1). The collected desired fractions wereconcentrated under vacuum to give white solid. The residue was purifiedby prep-HPLC (column: Phenomenex Gemini 150*25 mm*10 um; mobile phase:[water (10 mM NH₄HCO₃)-ACN]; B %: 35%-65%, 3 min) and (column: BostonGreen ODS 150*30 5 u; mobile phase: [water (0.225% Formic Acid)-ACN]; B%: 15%-45%, 10 min). The desired fractions were pooled and lyophilizatedto give2-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1H-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(2.99 mg, 5.50 umol). ES+APCI MS m/z 544.5 [M+H]⁺. ¹H NMR (400 MHz,chloroform-d) δ=8.36 (br s, 1H), 8.09 (s, 1H), 7.29 (br s, 1H),7.24-7.20 (m, 1H), 6.62 (br d, J=13.6 Hz, 1H), 6.47-6.24 (m, 1H), 5.83(br d, J=10.8 Hz, 1H), 5.50 (br s, 1H), 5.08 (br s, 1H), 4.60 (br s,1H), 4.31 (s, 2H), 4.12 (br d, J=14.4 Hz, 1H), 3.99 (br d, J=10.8 Hz,1H), 3.55 (br t, J=5.6 Hz, 2H), 3.42-3.29 (m, 1H), 3.10 (br s, 1H),3.00-2.68 (m, 7H), 2.49 (s, 6H), 2.43 (s, 3H), 1.39 (d, J=6.0 Hz, 3H).

Example 1532-[4-[7-(3-hydroxy-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 773 umol) and3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propan-1-ol (219 mg,1.39 mmol) in toluene (10 mL) was added tBuONa (111 mg, 1.16 mmol) underN₂. The reaction mixture was stirred at 18° C. for 0.5 hour. Uponcompletion, the mixture was purified by silica gel chromatography(PE:EtOAc=3:1 to 0:1 then EA:MeOH=50:1 to 10:1) followed by reversedflash chromatography (50% to 90% MeCN in water, base condition) to givetert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(120 mg. 156 umol, 20.5% yield, 97.9% purity) as a brown solid ¹H NMR(400 MHz, CHLOROFORM-d) δ=8.19-8.12 (m, 1H), 7.83-7.77 (m, 1H),7.55-7.43 (m, 2H), 7.29 (d, J=1.6 Hz, 1N), 6.84 (d, J=2.0 Hz, 1H), 4.64(br s, 1H), 4.42-4.35 (m, 3H), 4.26 (br d, J=5.2 Hz, 2H), 4.12-4.03 (m,3H), 3.96 (br d, J=12.8 Hz, 1H), 3.62 (dd, J=1.6, 7.6 Hz, 1H), 3.50 (brs, 2H), 3.31 (br d, J=13.6 Hz, 3H), 3.11-2.97 (m, 2H), 2.94 (br d, J=8.8Hz, 1H), 2.89-2.69 (m, 5H), 2.54 (br d, J=9.8 Hz, 1H), 2.00-1.92 (m,2H), 1.90-1.83 (m, 1H), 1.73 (br d, J=10.0 Hz, 1H), 1.53 (s, 9H), 1.41(s, 9H)

Step B:4-[4-[3-(cyanomethyl)piperazin-1-yl]-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate: A solution of tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(120 mg, 162 umol) in TFA (370 mg, 3.24 mmol, 240 uL) was stirred at 18°C. for 1 hour. Upon completion, the solvent was removed under vacuum togive4-[4-[3-(cyanomethyl)piperazin-1-yl]-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate(140 mg, 161 umol, 99.5% yield, 2 TFA) as brown oil.

Step C:[4-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate: To a solution of[4-[4-[3-(cyanomethyl)piperazin-1-yl]-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate(140 mg, 161 umol) and DIEA (167 mg, 1.29 mmol, 225 uL) in DCM (2 mL)was added prop-2-enoyl prop-2-enoate (30.5 mg, 242 umol) at 0° C. Thereaction mixture was stirred at 18° C. for 1 hour. Upon completion, thereaction mixture was quenched by addition of water (5 mL) and theaqueous layer extracted with DCM (3×10 mL). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated under vacuum. Theresidue was purified by reversed flash (Base condition, MeCN/NH₃·H₂O inwater: 50% to 80%) to give[4-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (60 mg, 86.5 umol, 53.6% yield). ¹H NMR (400 MHz,CHLOROFORM-d) δ 8.22-8.13 (m, 1H), 7.84-7.78 (m, 1H), 7.56-7.45 (m, 2H),7.31 (d, J=2.0 Hz, 1H), 6.86 (d, J=2.4 Hz, 1H), 6.62 (br s, 1H),6.47-6.37 (m, 1H), 5.92-5.79 (m, 1H), 5.24-4.88 (m, 1H), 4.75 (br s,1H), 4.45-4.36 (m, 3H), 4.31-4.20 (m, 2H), 4.15 (br d, J=13.6 Hz, 1H),4.10-4.01 (m, 2H) 3.64 (dd, J=1.6, 7.6 Hz, 2H), 3.51 (br s, 2H), 3.38(br s, 2H), 3.14 (br s, 1H), 3.08-2.73 (m, 7H), 2.56 (br d, J=10.0 Hz,1H), 2.03-1.93 (m, 2H), 1.88 (br d, J=9.6 Hz, 1H), 1.78-1.70 (m, 1H),1.61 (s, 9H), 1.43 (s, 9H).

Step D:2-[4-[7-(3-hydroxy-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile:To a solution of[4-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (60 mg, 86.5 umol) in THF (0.5 ML) was added NaOH(2 M, 600 uL). The reaction mixture was stirred at 18° C. for 12 hours.Upon completion, the reaction mixture was acidified by addition of 4drops of HCOOH (20% in water) and the aqueous layer was extracted withDCM (5×8 mL). The combined organics were dried over Na₂SO₄ andconcentrated under vacuum. The residue was purified by prep-HPLC(column: Luna C18 150*25 5 u; mobile phase: [water (0.225% FormicAcid)-ACN]; B %: 10%-40%, 10 min) to give2-[4-[7-(3-hydroxy-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(19.8 mg, 28.3 umol, 32.8% yield, 93.8% purity, Formic Acid salt) wasobtained as a brown solid. ES+APCI MS m/z 610.5 [M+H]⁻.

Example 1542-[4-[7-(1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A:tert-butyl2-(cyanomethyl)-4-[2-methylsulfanyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To the solution of tert-butyl2-(cyanomethyl)-4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(3 g, 7.42 mmol), 1-bromonaphthalene (3.07 g, 14.8 mmol, 2.06 mL) andCs₂CO₃ (7.25 g, 22.2 mmol) in toluene (60 mL) was added XPhospalladacycle gen 3 (628 mg, 742 umol) under N₂ and the suspension wasdegassed under vacuum and purged with N₂ several times. The mixture waswarmed to 70° C. and stirred at 70° C. for 10 hours. The resultingmixture was filtered and the filter cake was washed with EtOAc (3×20mL). The combined organics were concentrated under reduced pressure togive a residue. The residue was purified by silica gel chromatography(PE:EtOAc from 50:1 to 3:1) to givetert-butyl2-(cyanomethyl)-4-[2-methylsulfanyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(3.55 g, 6.02 mmol, 81.2% yield, 90.0% purity) as brown oil. ES+APCI MSm/z 531.4 [M+H]⁺.

Step B: tert-butyl2-(cyanomethyl)-4-[2-methylsulfinyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To the solution of tert-butyl2-(cyanomethyl)-4-[2-methylsulfanyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(2.95 g, 5.56 mmol) in DCM (60 mL) was added m-CPBA (1.13 g, 5.56 mmol,85.0% purity) at 0° C. and stirred at 0° C. for 1 hour. The reactionmixture was quenched by addition of saturated Na₂S₂O₃ (20 mL) at 0° C.and layers were separated, and the aqueous layer diluted with water (20mL) and extracted with EtOAc (60 mL). The combined organic layers weredried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure to give a residue. The residue was purified by reversed phaseflash column (ACN/Water (0.1% Formic Acid)=100%) to give tert-butyl2-(cyanomethyl)-4-[2-methylsulfinyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1.7 g, 2.80 mmol, 50.3% yield, 90.0% purity) as brown solid ES+APCI MSm/z 574.4 [M+H]⁺.

Step C: tert-butyl2-(cyanomethyl)-4-[7-(1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of tert-butyl2-(cyanomethyl)-4-[2-methylsulfinyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(300 mg, 549 umol,) and3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propan-1-ol (160 mg,1.02 mmol) in toluene (6 mL) was added tBuONa (79.1 mg, 823 umol). Thereaction mixture was stirred at 18° C. for 0.5 hour. Upon completion,the reaction mixture was purified by silica gel chromatography(PE:EA=3:1 to 0:1 then EA:MeOH=50:1 to 10:1) to give tert-butyl2-(cyanomethyl)-4-[7-(1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 249 umol, 45.3% yield, 79.6%, purity) was obtained as a brownsolid. ES+APCI MS m/z 640.5 [M+H]⁺.

Step D:2-[4-[7-(1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile:A reaction mixture of tert-butyl2-(cyanomethyl)-4-[7-(1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 313 umol) in TFA (770 mg, 6.75 mmol, 500 uL) was stirred at 18°C. for 1 hour. Upon completion the solvent was removed under vacuum togive2-[4-[7-(1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(271 mg, crude) as a brown oil.

Step E:2-[4-[7-(1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile:To a solution of2-[4-[7-(1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(271 mg, 502 umol) and DIEA (323 mg, 2.50 mmol, 0.435 mL) in DCM (6 mL)was added prop-2-enoyl prop-2-enoate (60 mg, 476 umol) at 0° C. and thereaction mixture stirred at 18° C. for 1 hour. Upon completion, thereaction mixture was quenched by addition of a drop of water andpurified by silica gel chromatography (PE:EtOAC=3:1 to 0:1) then prepHPLC (column: Gemini 150*25 5 u; mobile phase: [water (0.05% ammoniahydroxide v/v)-ACN]; B %: 33%-63%, 12 min) to give2-[4-[7-(1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(23.8 mg, 40.0 umol, 7.97% yield) as yellow solid. ES+APCI MS m/z 594.5[M+H]⁺.

Example 155(S)-1-(4-(7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: tert-butyl4-[7-benzyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a mixture of [(2S)-1-methylpyrrolidin-2-yl]methanol (4.15 g, 36.0mmol, 4.28 mL) in THF (100 mL) was added NaH (2.16 g, 54.06 mmol, 60%purity) in portions at 0° C. After the mixture was stirred at 0° C. for1 hour, a solution oftert-butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(8.0 g, 18.02 mmol) in THF (60 mL) was added and the mixture was stirredat 70° C. for 11 hours. After completion, the reaction mixture waspoured into aqueous NH₄Cl (160 mL), and the aqueous layer extracted withEtOAc (2×100 mL). The combined organics were dried over Na₂SO₄, filteredand concentrated in vacuo. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=3/1 to Ethylacetate/Methanol=10:1) to give tert-butyl4-[7-benzyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(4.9 g, 8.70 mmol, 48.3% yield, 92.8% purity) as gray solid. ES+APCI MSm/z 523.2 [M+H]⁺

Step B: tert-butyl 4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a mixture of tert-butyl4-[7-benzyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(2.20 g, 4.21 mmol) in MeOH (30 mL) was added Pd(OH)₂/C (700 mg, 10%purity) and the mixture was degassed under vacuum and purged with H₂several times and the reaction stirred at 40° C. for 12 hours under H₂(15 Psi). After completion, the reaction mixture was filtered throughcelite and the filtrate concentrated to give tert-butyl4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1.80 g, 4.02 mmol, 95.6% yield, 96.7% purity) as black solid. ES+APCIMS m/z 433.1 [M+H]⁺.

Step C: tert-butyl4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a mixture of tert-butyl4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 462 umol) and 4-bromo-5-methyl-1-tetrahydropyran-2-yl-indazole(204 mg, 694 umol) in toluene (4 mL) was added Pd₂(dba)₃ (63.5 mg, 69.4umol), RuPhos (43.2 mg, 92.5 umol) and Cs₂CO₃ (301 mg, 925 umol) and themixture stirred at 110° C. for 12 hours under N₂. After completion, thereaction mixture was partitioned between water (10 mL) and EtOAc and thelayers separated. The aqueous layer was subsequently extracted withEtOAc (2×10 mL) and the combined organics were dried over Na₂SO₄,filtered and concentrated. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=5/1 to Ethylacetate/MeOH=10/1) to give tert-butyl4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(240 mg, 310 umol, 67.1% yield, 83.6% purity) as brown oil. ES+APCI MSm/z 647.6 [M+H]⁺.

Step D:7-(5-methyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine:To a mixture of tert-butyl4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(240 mg, 371 umol) in DCM (1 mL) was added TFA (1.54 g, 13.5 mmol, 1 mL)and the mixture stirred at 15° C. for 1 hour. After completion, thereaction mixture was concentrated to give7-(5-methyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(250 mg, 309 umol, 83.4% yield, 85.5% purity, 2 TFA) as brown solidwhich was used for the next step without further purification. ES-APCIMS m/z 463.4 [M+H]⁺.

Step E:1-[4-[7-(5-methyl-1H-indazol-4-yl)-2-[[(23)-1-methylpyrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a mixture of7-(5-methyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(250 mg, 362 umol, 2 TFA) in DCM (2 mL) was added DIEA (702 mg, 5.43mmol, 946 uL) and the mixture cooled to −50° C. Prop-2-enoylprop-2-enoate (36.5 mg, 289 umol) was added in portions to the reactionat −50° C. and the mixture stirred at −50° C. for 30 minutes. Aftercompletion, the reaction mixture was quenched by addition of MeOH (1 mL)and the mixture concentrated. The residue was taken up in DCM (10 mL)and the organics washed with H₂O (2×8 mL). The organics were dried overNa₂SO₄, filtered and concentrated. The residue was purified by prep-HPLC((Instrument: gx-1; Column: Phenomenex Gemini C18 250*50 mm*10 um;Condition: water (0.05% ammonia hydroxide v/v)-ACN; Begin B: 32; End B:62; Gradient Time (min): 12; 100% B Hold Time (min): 2; FlowRate(ml/min): 25) to give1-[4-[7-(5-methyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(48.6 mg, 92.9 umol, 25.7% yield, 98.7% purity) as yellow solid. ES+APCIMS m/z 517.5 [M+H]⁺.

Example 156(S)-1-(4-(2-((1-methylpyrrolidin-2-yl)methoxy)-7-(5-(trifluoromethyl)-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

(S)-1-(4-(2-((1-methylpyrrolidin-2-yl)methoxy)-7-(5-(trifluoromethyl)-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-onewas prepared following Example 155 substituting4-bromo-1-tetrahydropyran-2-yl-5-(trifluoromethyl)indazole (Intermediate60) for 4-bromo-5-methyl-1-tetrahydropyran-2-yl-indazole in Step C.ES+APCI MS m/z 571.4 [M+H]⁺.

Example 157(S)-1-(4-(7-(5-methoxy-1H-indazol-4-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

(S)-1-(4-(7-(5-methoxy-1H-indazol-4-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-onewas prepared following Example 155 substituting4-bromo-5-methoxy-1-tetrahydropyran-2-yl-indazole for4-bromo-5-methyl-1-tetrahydropyran-2-yl-indazole in Step C. ES+APCI MSm/z 533.4 [M+H]⁺.

Example 1581-[4-[7-(2-isopropylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: tert-butyl4-[7-(2-isopropylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:tert-butyl4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 462 umol), 1-bromo-2-isopropyl-benzene (120 mg, 601 umol),Cs₂CO₃ (452 mg, 1.39 mmol) and XPHOS PALLADACYCLE GEN 3 (78.3 mg, 92.5umol) in toluene (4.00 mL) was de-gassed with N₂ and then heated to 100°C. for 10 hours under N₂. Upon completion, the mixture was filtered andthe filtrate was concentrated. The crude product was purified by silicagel chromatography eluted with EtOAc/MeOH=50/1 to 5/1 to give tert-butyl4-[7-(2-isopropylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(84.6 mg, 134 umol, 28.9% yield, 87.0% purity) as a yellow solid.ES+APCI MS m/z 551.2 [M+H]⁺.

1-[4-[7-(2-isopropylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-onewas prepared following Example 155 substituting tert-butyl4-[7-(2-isopropylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylatefor tert-butyl4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylatein Step D. ES+APCI MS m/z 505.6 [M+H]⁺.

Example 159(S)-1-(4-(2-((1-methylpyrrolidin-2-yl)methoxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

(S)-1-(4-(2-((1-methylpyrrolidin-2-yl)methoxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-onewas prepared following Example 155 substituting1-bromo-2-(trifluoromethyl)benzene for4-bromo-5-methyl-1-tetrahydropyran-2-yl-indazole in Step C. ES+APCI MSm/z 531.5 [M+H]⁺.

Example 1601-(4-(7-(5-methyl-1H-indazol-4-yl)-2-(3-(piperidin-1-yl)propoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: Benzyl4-[2-methylsulfanyl-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:A mixture of benzyl 4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (3.15 g, 7.88 mmol),2-[(4-bromo-5-methyl-indazol-1-yl)methoxy]ethyl-trimethyl-silane (3.50g, 10.2 mmol), Cs₂CO₃ (6.42 g, 19.70 mmol), Pd₂(dba)₃ (1.08 g, 1.18mmol) and RuPhos (735 mg, 1.58 mmol) in toluene (50 mL) was degassed andwith N₂ 3 times and the mixture stirred at 90° C. for 10 hours under N₂atmosphere. The reaction mixture was quenched by addition of water (100mL) and the aqueous layer extracted with ethyl acetate (3×100 mL). Thecombined organics were washed with brine (50 mL), dried over Na₂SO₄,filtered and concentrated under reduced. The residue was purified bycolumn chromatography using 1→33% EtOAc/Petroleum Ether to give benzyl4-[2-methylsulfanyl-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(2.30 g, 2.93 mmol, 37.1% yield). ES+APCI MS m/z 660.3 [M+H]⁺.

Step B: benzyl 4-[2-methylsulfinyl-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a stirred solution of benzyl4-[2-methylsulfanyl-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(2.30 g, 3.49 mmol) in DCM (20 mL) was added m-CPBA (601 mg, 3.49 mmol)at 0° C. The reaction mixture was stirred at 0° C. for 1 hour under N2atmosphere. The reaction mixture was quenched by addition Na₂S₂O₃ (10mL) at 0° C. and then diluted with water (100 mL) and the aqueous layerextracted with DCM (200 mL). The combined organics were washed withbrine (200 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by column chromatographyusing 1→10% MeOH/DCM as eluent to give benzyl4-[2-methylsulfinyl-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(2.00 g, 2.84 mmol, 81.4% yield). ES+APCI MS m/z 676.3 [M+H]⁺.

Step C: benzyl4-[7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-2-[3-(1-piperidyl)propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a mixture of benzyl4-[2-methylsulfinyl-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 739 umol) and 3-(1-piperidyl)propan-1-ol (211 mg, 1.48 mmol) inTHF (10 mL) was added t-BuONa (213 mg, 2.22 mmol) portion wise and themixture stirred at 20° C. for 1 hour under N₂ atmosphere. The mixturewas cooled to 0° C. and HCl (2M) was added until the pH˜7. The mixturewas filtered and filtrate was concentrated in vacuo. The residue waspurified by reversed phase flash using water 5→95% 0.5%TFA/water/acetonitrile as eluent to give benzyl4-[7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-2-[3-(1-piperidyl)propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(300 mg, 385 umol, 52.1% yield). ES+APCI MS m/z 755.4 [M+H]⁺.

Step D:7-(5-methyl-1H-indazol-4-yl)-4-(piperazin-1-yl)-2-(3-(piperidin-1-yl)propoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine:To a solution of benzyl 4-[7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-2-[3-(1-piperidyl)propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(300 mg, 397 umol) in MeOH (20 mL) was added HCl/MeOH (4 M, 1.99 mL) andPd(OH)₂ (200 mg, 10% purity) under N₂. The suspension was degassed undervacuum and purged with H₂ several times. The mixture was stirred underH₂ (15 psi) at 25° C. for 1 hour. The reaction mixture was filtered andthe filtrate was concentrated to give7-(5-methyl-1H-indazol-4-yl)-4-(piperazin-1-yl)-2-(3-(piperidin-1-yl)propoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine(250 mg, 360 umol, 90.7% yield).

Step E:1-[4-[7-(5-methyl-1H-indazol-4-yl)-2-[3-(1-piperidyl)propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a mixture of7-(5-methyl-1H-indazol-4-yl)-4-(piperazin-1-yl)-2-(3-(piperidin-1-yl)propoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine(250 mg, 360 umol, 2HCl) and DIEA (465 mg, 3.60 mmol, 629 uL) in DCM(8.00 mL) was added a solution of prop-2-enoyl prop-2-enoate (36.3 mg,288 umol) in DCM (2.00 mL) at −40° C. under nitrogen atmosphere and thereaction stirred for 1 hour. The reaction mixture was quenched byaddition NaHCO₃ (500 uL) at −40° C., and then diluted with water (10 mL)and the aqueous layer extracted with DCM (10 ml). The organics weredried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography (SiO2, DCM/MeOH 1/0 to5/1) and further purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10 um; mobile phase: [water (0.225% Formic Acid)-ACN], B %:8%-28%, 10 min) to give1-[4-[7-(5-methyl-1H-indazol-4-yl)-2-[3-(1-piperidyl)propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(16.0 mg, 29.1 umol, 8.07% yield). ES+APCI MS m/z 545.3 [M+H]⁺.

Example 1611-[4-[7-(5-methyl-1H-indazol-4-yl)-2-[(1-methylpyrrolidin-3-yl)methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

1-[4-[7-(5-methyl-1H-indazol-4-yl)-2-[(1-methylpyrrolidin-3-yl)methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-onewas prepared following Example 160 substituting(1-methylpyrrolidin-3-yl)methanol for 3-(1-piperidyl)propan-1-ol in StepC. ES+APCI MS m/z 517.4 [M+H]⁺.

Example 1621-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1H-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: benzyl4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:A mixture of (2R)-1-(dimethylamino)propan-2-ol (183 mg, 1.78 mmol) (8.00mL), benzyl4-[2-methylsulfinyl-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(400 mg, 592 umol) and NaOtBu (114 mg, 1.18 mmol) in toluene werestirred at 15° C. for 0.5 hour. The reaction mixture was filtered andthe filtrate was concentrated under vacuum. The residue was purified bycolumn chromatography over Al₂O₃ (Petroleum Ether/EthylAcetate 10/1 to0/1) to give benzyl4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(280 mg, 352 umol). ¹H NMR (400 MHz, chloroform-d) δ=8.08 (s, 1H),7.46-7.39 (m, 5H), 7.38-7.33 (m, 2H), 5.76 (s, 2H), 5.43-5.33 (m, 1H),5.24 (s, 2H), 4.35 (s, 2H), 3.72-3.67 (m, 4H), 3.64-3.56 (m, 4H),3.55-3.47 (m, 4H), 2.87-2.80 (m, 2H), 2.74 (dd, J=6.8, 12.8 Hz, 1H),2.49 (s, 3H), 2.47-2.40 (m, 1H), 2.36 (s, 6H), 1.42 (d, J=6.4 Hz, 3H),0.98-0.92 (m, 2H), 0.00 (s, 9H).

Step B: tert-butyl4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of benzyl4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 280 umol) and (Boc)₂O (122 mg, 559 umol, 129 uL) in MeOH (6.00mL) was added 10% Pd/C (80 mg) under N₂. The suspension was degassedunder vacuum and purged with H₂ several times. The mixture was stirredunder H₂ (15 psi) at 25° C. for 1 hour and 35° C. for 1 hour. Uponcompletion, the mixture was filtered and the filtrate concentrated undervacuum to give mixture of tert-butyl4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylateand(2R)—N,N-dimethyl-2-[[7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propan-1-amineas a mixture (110 mg). ES+APCI MS m/z 681.3 [M+H]⁺.

Step C:(2R)—N,N-dimethyl-2-[[7-(5-methyl-1H-indazol-4-yl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propan-1-amine:(2R)—N,N-dimethyl-2-[[7-(5-methyl-1H-indazol-4-yl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propan-1-amine(TFA) and[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-5-methyl-indazol-1-yl]methanol.A solution of 110 mg mixture of tert-butyl4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylateand(2R)—N,N-dimethyl-2-[[7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propan-1-aminein TFA (3.08 g, 27.0 mmol) was stirred at 30° C. for 1 hour. Uponcompletion, the mixture was concentrated under vacuum to give 260 mgmixture of(2R)—N,N-dimethyl-2-[[7-(5-methyl-1H-indazol-4-yl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propan-1-amineand[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-5-methyl-indazol-1-yl]methanol.ES+APCI MS m/z 451.3 [M+H]⁺.

Step D:1-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1H-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a solution of 260 mg mixture of(2R)—N,N-dimethyl-2-[[7-(5-methyl-1H-indazol-4-yl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propan-1-amineand[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-5-methyl-indazol-1-yl]methanolin DCM (1.00 mL) cooled to −50° C. was added DIEA (594 mg, 4.59 mmol)followed by prop-2-enoyl prop-2-enoate (18.0 mg, 143 umol) dropwise andthe mixture was stirred at between −50° C. to −40° C. for 30 minutes.Upon completion, the mixture was concentrated under vacuum to give 100mg mixture of1-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1H-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-oneand1-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-[1-(hydroxymethyl)-5-methyl-indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one.ES+APCI MS m/z 505.4 [M+H]⁺.

Step E:1-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1H-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:A mixture of 100 mg of1-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1H-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-oneand1-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-[1-(hydroxymethyl)-5-methyl-indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-onein THF (22 mL) and water (550 uL) was added NaOH (44.8 mg, 1.12 mmol)and the mixture stirred at 10° C. for 3 hours. Upon completion, themixture was concentrated under vacuum. The residue was diluted withwater (1 mL) and extracted with DCM (3×5 mL). The combined organics weredried over Na₂SO₄ and concentrated under vacuum. The residue waspurified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um;mobile phase: [water (0.225% Formic Acid)-ACN]; B %: 10%-40%, 12 min) togive1-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1H-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(16.2 mg, 29.2 umol, 99.0% purity, Formic Acid Salt) as a off-whitesolid. ES+APCI MS m/z 505.2 [M+H]⁺.

Example 1631-(4-(2-(2-(diethylamino)ethoxy)-7-(5-methyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: benzyl4-[2-[2-(diethylamino)ethoxy]-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a mixture of benzyl4-[2-methylsulfinyl-7-[5-methyl-1-(2-trimethylsilylethoxymmethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 739 umol) and 2-(diethylamino)ethanol (173 mg, 1.48 mmol, 197uL) in THF (10 mL) was added t-BuONa (213 mg, 2.22 mmol), and themixture stirred at 20° C. for 1 hour under Ni atmosphere. The mixturewas cooled to 0° C. and HCl (2 M) was added until pH˜7. The mixture wasfiltered and the filtrate was concentrated in vacuo. The residue waspurified by column chromatography using 0→10% MeOH/DCM as eluent to giveimpure material which was further purified by reversed phasechromatography to give benzyl4-[2-[2-(diethylamino)ethoxy]-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(220 mg, 295 umol, 39.9% yield). ES+APCI MS m/z 729.3 [M+H]⁺.

Step B:N,N-diethyl-2-[[7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]ethanamine:To a solution of benzyl4-[2-[2-(diethylamino)ethoxy]-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(120 mg, 164 umol) in MeOH (10 mL) was added Pd(OH)₂ (99.4 mg, 10%purity) and HCl/MeOH (4 M, 823.05 uL) under N₂. The suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred under H₂ (15 psi) at 25° C. for 1 hour. The mixture wasconcentrated in vacuo to giveN,N-diethyl-2-[[7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]ethanamine(105 mg, 157.24 umol). ES+APCI MS m/z 595.4 [M+H]⁺.

Step C:1-[4-[2-[2-(diethylamino)ethoxy]-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a mixture of N,N-diethyl-2-[[7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]ethanamine(105 mg, 158 umol, 2 HCl) and DIEA (204 mg, 1.58 mmol, 276 uL) in DCM (8mL) at −40° C. was added a solution of prop-2-enoyl prop-2-enoate (15.9mg, 126.4 umol) in DCM (2 mL) under nitrogen atmosphere and the reactionstirred for 1 hour. The reaction mixture was quenched by addition NaHCO₃(500 uL) at −40° C., and then diluted with water (10 mL). The aqueouslayer was extracted with DCM (10 ml), dried over NaSO₄, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography using 0→20% MeOH/DCM as eluent to give1-[4-[2-[2-(diethylamino)ethoxy]-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(60.0 mg, 71.2 umol, 45.0% yield). ES+APCI MS m/z 649.3 [M+H]⁺.

Step D:1-[4-[2-[2-(diethylamino)ethoxy]-7-(5-methyl-1H-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a solution of1-[4-[2-[2-(diethylamino)ethoxy]-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(50 mg, 77.0 umol) in DCM (500 uL) was added TFA (175 mg, 1.54 mmol, 114uL). The mixture was stirred at 15° C. for 16 hours. The reactionmixture was concentrated under vacuum and the residue purified byprep-HPLC (column: Phenomenex Gemini C18 250*50 mm*10 um; mobile phase:[water (0.05% ammonia hydroxide v/v)-ACN]; B %: 32%-62%, 12 min) to give1-[4-[2-[2-(diethylamino)ethoxy]-7-(5-methyl-1H-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(16.0 mg, 30.2 umol, 39.2% yield). ES+APCI MS m/z 519.3 [M+H]⁺.

Example 1641-(4-(7-(5-methyl-1H-indazol-4-yl)-2-(2-(piperidin-1-yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)ethanone

Step A: benzyl 4-[7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of benzyl4-[2-methylsulfinyl-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 739 umol) and 2-(1-piperidyl)ethanol (191 mg, 1.48 mmol, 197uL) in toluene (20 mL) was added t-BuONa (213 mg, 2.22 mmol). Themixture was stirred at 20° C. for 1 hour under N₂ atmosphere. Themixture was cooled to 0° C. and HCl (2 M) was added until pH˜7. Themixture was filtered and the filtrate concentrated in vacuo. The residuewas purified by column chromatography using 0→10% MeOH/DCM as eluent togive benzyl 4-[7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(300 mg, 404 umol, 54.7% yield). ES+APCI MS m/z 741.4 [M+H]⁺.

Step B:7-(5-methyl-1H-indazol-4-yl)-4-piperazin-1-yl-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine:A solution of benzyl 4-[7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(250 mg, 337 umol) in TFA (10 mL) was stirred at 80° C. for 1 hour. Thereaction mixture was concentrated under vacuum to give7(5-methyl-1H-indazol-4-yl)-4-piperazin-1-yl-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(200 mg, 283 umol, 84.1% yield). ES+APCI MS m/z 477.3 [M+H]⁺.

Step C:1-[4-[7-(5-methyl-1H-indazol-4-yl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a mixture of7-(5-methyl-1H-indazol-4-yl)-4-piperazin-1-yl-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(200 mg, 283 umol, 2 TFA) and DIEA (366 mg, 2.84 mmol, 495 uL) in DCM (8mL) at −40° C. was added a solution of prop-2-enoyl prop-2-enoate (28.6mg, 227 umol) DCM (2 mL) under nitrogen atmosphere and the reactionstirred for 1 hour. The reaction mixture was quenched by addition NaHCO₃(500 uL) at −40° C., and then diluted with water (10 mL) and DCM (10ml). The separated organic layer was dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byprep-HPLC (column: Phenomenex Gemini C18 250*50 mm*10 um; mobile phase:[water (0.05% ammonia hydroxide v/v)-ACN]; B %: 30%-60%, 12 min),1-[4-[7-(5-methyl-1H-indazol-4-yl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(600 mg, 11.1 umol, 3.94% yield, 99.0% purity). ES+APCI MS m/z 531.4[M+H]⁺.

Example 1651-[4-[7-(2-fluoro-3-hydroxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: 3-methoxynaphthalen-1-ol: To a solution of naphthalene-1,3-diol(20 g, 125 mmol) in MeOH (150 mL) was added HC/MeOH (4 M, 250 mL) at 0°C. The mixture was warmed up to 18° C. and stirred for 36 hours. Themixture was concentrated under vacuum. The residue was purified bycolumn chromatography over silica gel (petroleum ether/ethyl acetate100/1 to 1/1). The desired fractions were collected and concentratedunder vacuum to give 3-methoxynaphthalen-1-ol (11 g, 62.5 mmol, 50.1%yield, 99% purity) as a light yellow solid. ES+APCI MS m/z 175.1 [M+H]⁺.

Step B: 4-bromo-3-methoxy-naphthalen-1-ol: To a solution of3-methoxynaphthalen-1-ol (0.50 g, 2.87 mmol) in THF (10 mL) was added asolution of NBS (562 mg, 3.16 mmol) in THF (3.00 mL) at 0° C. Afterstirring at 0° C. for 2 hours, the mixture was concentrated undervacuum, diluted with H₂O (5 mL), extracted with dichloromethane (3×10mL). The combined extracts were washed with saturated sodium chloride(1×20 mL), dried over Na₂SO₄, filtered and concentrated under vacuum.The residue was purified by column chromatography (SiO₂, petroleumether/ether acetate=3/1) to give 4-bromo-3-methoxy-naphthalen-1-ol (0.43g, 1.43 mmol, 49.7% yield) as a yellow solid. ES+APCI MS m/z 253 [M+H]⁺.

Step C: 4-bromo-2-fluoro-3-methoxy-naphthalen-1-ol: To a solution of4-bromo-3-methoxy-naphthalen-1-ol (4.00 g, 15.8 mmol) in acetonitrile(20 mL) was added a solution of1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2,2,2]octane;ditetrafluoroborate (6.72 g, 19.0 mmol) in acetonitrile (20 mL) at −40°C. After stirring at −40° C. for 1 hour and 10° C. for 3 hours, themixture was concentrated under vacuum. The residue was purified bycolumn chromatography (SiO₂, petroleum ether/ether acetate=3/1) to give4-bromo-2-fluoro-3-methoxy-naphthalen-1-ol (4.00 g, 10.6 mmol, 67.2%yield) as a yellow solid. ES+APCI MS m/z 271.0 [M+H]⁺.

Step D: 2-fluoro-3-methoxy-naphthalen-1-ol: A mixture of4-bromo-2-fluoro-3-methoxy-naphthalen-1-ol (2.00 g, 7.38 mmol) and 10%Pd/C (0.01 g) in ethyl acetate (20 mL) was stirred at 10° C. for 1 hourunder H₂ at 15 psi. The mixture was filtered and concentrated undervacuum to give 2-fluoro-3-methoxy-naphthalen-1-ol (1.60 g, crude) asyellow oil and used into next step without further purification. ES+APCIMS m/z 193.0 [M+H]⁺.

Step E: (2-fluoro-3-methoxy-1-naphthyl) trifluoromethanesulfonate: To asolution of 2-fluoro-3-methoxy-naphthalen-1-ol (1.60 g, crude) and TEA(1.85 g, 18.3 mmol, 2.55 mL) in dichloromethane (30 mL) was addedtrifluoromethylsulfonyl trifluoromethanesulfonate (2.35 g, 8.33 mmol,1.37 mL) at −78° C. for 1 hour. The mixture was quenched with saturatedammonium chloride (30 mL), extracted with ethyl acetate (3×20 mL),washed with saturated sodium chloride (1×50 mL), dried over Na₂SO₄,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography (SiO₂, petroleum ether/ether acetate 3/1) to give(2-fluoro-3-methoxy-1-naphthyl) trifluoromethanesulfonate (1.10 g, 2.07mmol, two steps 24.9% yield) as a yellow solid. ES+APCI MS m/z 324.9[M+H]⁺.

Step F: tert-butyl4-[7-(2-fluoro-3-methoxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:A mixture of tert-butyl4-[2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.40 g, 865 umol), (2-fluoro-3-methoxy-1-naphthyl)trifluoromethanesulfonate (561 mg, 1.73 mmol), RuPhos (80.7 mg, 173umol), Pd₂(dba)₃ (79.2 mg, 86.5 umol) and t-BuONa (249 mg, 2.59 mmol) intoluene (10 mL) was stirred at 110° C. for 5 hours under N₂. The mixturewas diluted with water (10 mL), extracted with ether acetate (3×10 mL).The extracts were washed with saturated sodium chloride (1×20 mL), driedover Na₂SO₄, filtered and concentrated under vacuum. The residue waspurified by reversed phase flash chromatography [water (0.1% FormicAcid)/acetonitrile] to give tert-butyl4-[7-(2-fluoro-3-methoxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.35 g, 495 umol, 57.2% yield) as a yellow oil. ES+APCI MS m/z 637.1[M+H]⁺.

Step G:4-[3-[[7-(2-fluoro-3-methoxy-1-naphthyl)-4-piperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propyl]morpholine:A mixture of tert-butyl4-[7-(2-fluoro-3-methoxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.40 g, 628 umol) and TFA (1.07 g, 9.42 mmol, 698 uL) indichloromethane (0.70 mL) was stirred at 10° C. for 1 hour. The mixturewas concentrated under vacuum to give4-[3-[[7-(2-fluoro-3-methoxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propyl]morpholine(0.41 g, crude, TFA) as a yellow oil and used into next step withoutfurther purification. ES+APCI MS m/z 537.5 [M+H]⁺.

Step H:1-[4-[7-(2-fluoro-3-methoxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a solution of4-[3-[[7-(2-fluoro-3-methoxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propyl]morpholine(0.41 g, crude, TFA salt) and TEA (635 mg, 6.27 mmol, 873 uL) indichloromethane (5.0 mL) was added prop-2-enoyl prop-2-enoate (79.1 mg,627 umol) at −40° C. After stirring at −40° C. for 0.5 h, the mixturewas quenched with methanol (0.10 mL) and concentrated under vacuum. Theresidue was purified by column chromatography (Al₂O₃,dichloromethane/methanol=10/1) to give1-[4-[7-(2-fluoro-3-methoxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(0.25 g, 411 umol, two steps 65.5% yield) as a yellow oil. ES+APCI MSm/z 591.0 [M+H]⁺.

Step I:1-[4-[7-(2-fluoro-3-hydroxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a solution of1-[4-[7-(2-fluoro-3-methoxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(0.20 g, 339 umol) in dichloromethane (4.00 mL) was added BBr₃ (424 mg,1.69 mmol, 163 uL) at −78° C. for 0.5 hour and stirred at 0° C. for 2hours. The mixture was quenched with saturated sodium bicarbonate (5 mL)at −78° C. and stirred at 0° C. for 0.5 h. The mixture was extractedwith dichloromethane (3×10 mL) and concentrated under vacuum. Theresidue was purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10 um; mobile phase: [water (0.225% Formic Acid)-ACN]; B %:13%-45%, 7 min) to give1-[4-[7-(2-fluoro-3-hydroxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(35.2 mg, 60.8 umol, 17.9% yield, 99.4% purity) as a yellow solid.ES+APCI MS m/z 577.0[M+H]⁺.

Example 1661-[4-[7-(6-hydroxy-2-methyl-1,3-benzothiazol-4-yl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: 4-triisopropylsilyloxyaniline: To a solution of 4-aminophenol(5.00 g, 45.8 mmol, 7.14 mL) in DCM (50.0 mL) was added imidazole (4.06g, 59.6 mmol). TIPSCl (13.3 g, 68.7 mmol, 14.7 mL) was added to themixture dropwise. The mixture was stirred at 15° C. for 12 hours. Uponcompletion, the reaction mixture was filtered and the filtrate wasconcentrated under vacuum. The residue was purified by automated flashchromatography system (PE/EA 100/1 to 3/1) to give4-triisopropylsilyloxyaniline (9.46 g, 33.9 mmol, 73.9% yield, 95.0%purity) as a black oil.

¹H NMR (400 MHz, chloroform-d) δ=6.74-6.71 (m, 1H), 6.71-6.69 (m, 1H),6.60-6.58 (m, 1H), 6.58-6.55 (m, 1H), 3.66-2.98 (m, 2H), 1.28-1.16 (m,3H), 1.11-106 (m, 18H)

Step B: 2,6-dibromo-4-triisopropylsilyloxy-aniline: To a solution of4-triisopropylsilyloxyaniline (7.30 g, 27.5 mmol) in DCM (73.0 mL) andMeOH (73.0 mL) was added Br₂ (11.0 g, 68.8 mmol, 3.55 mL) in DCM (5 mL)dropwise at 0° C. The mixture was stirred at 15° C. for 5 hours. Uponcompletion, the mixture was diluted with sodium sulfite solution (60 mL)and extracted with DCM (3×200 mL). The organic layers were dried overNa₂SO₄ and concentrated under vacuum. The residue was purified by columnchromatography (PE/EA 50/1 to 1/1) to give2,6-dibromo-4-triisopropylsilyloxy-aniline (10.8 g, 23.2 mmol, 84.4%yield, 90.8% purity) as a brown oil. ES+APCI MS m/z 423.9[M+H]⁺.

Step C: N-(2,6-dibromo-4-triisopropylsilyloxy-phenyl)acetamide: To asolution of 2,6-dibromo-4-triisopropylsilyloxy-aniline (10.4 g, 24.6mmol) and CH₃COOH (52 mL) was added acetic anhydride (10.9 g, 107 mmol,10 mL). The reaction mixture was stirred at 90° C. for 1 hour. Uponcompletion, water (100 mL) and DCM (200 mL) were added and layers wereseparated. The aqueous phase was extracted with DCM (100 mL×2). Thecombined extracts were washed with 5% Na₂CO₃ (80 mL), washed with brine(100 mL), dried over Na₂SO₄ and concentrated under vacuum. The residuewas purified by column chromatography (PE/EA 50/1 to 1:1) to giveN-(2,6-dibromo-4-triisopropylsilyloxy-phenyl)acetamide (7.32 g, 14.2mmol, 57.6% yield, 90.0% purity) as a brown solid.

¹H NMR (400 MHz, chloroform-d) δ=7.16 (s, 1H), 7.11 (s, 2H), 2.21 (s,3H), 1.28-1.24 (m, 3H), 1.12-1.09 (m, 18H).

Step D: N-(2,6-dibromo-4-triisopropylsilyloxy-phenyl)thioacetamide: To asolution of N-(2,6-dibromo-4-triisopropylsilyloxy-phenyl)acetamide (7.22g, 15.5 mmol) in toluene (116 mL) was added LAWESSON'S REAGENT (3.14 g,7.76 mmol). The mixture was heated to 110° C. for 2 hours. Uponcompletion, the mixture was concentrated under vacuum. The residue waspurified by column chromatography (PE/EA 100/1 to 1/1)N-(2,6-dibromo-4-triisopropylsilyloxy-phenyl)thioacetamide (5.41 g, 8.40mmol, 54.1% yield, 74.7% purity) as a yellow oil. ES+APCI MS m/z481.9[M+H]⁺.

Step E: 4-bromo-2-methyl-1,3-benzothiazol-6-ol: CuI (94.2 mg, 494 umol)was added to a solution ofN-(2,6-dibromo-4-triisopropylsilyloxy-phenyl)thioacetamide (2.38 g, 4.94mmol), 1,10-phenanthroline (134 mg, 741 umol) and Cs₂CO₄ (4.83 g, 14.8mmol) in DME (48.0 mL). Then the reaction mixture was stirred at 80° C.for 12 hours under N₂. Upon completion, the reaction mixture wasfiltered and the filtrate was concentrated. The residue was purified bycolumn chromatography (PE/EA 50/1 to 0/1) to give4-bromo-2-methyl-1,3-benzothiazol-6-ol (1.33 g, 3.54 mmol, 71.7% yield,65.0% purity) as a brown oil.

¹H NMR (400 MHz, DMSO-d₆) δ=7.33 (d, J=2.4 Hz, 1H), 7.14 (d, J=2.4 Hz,1H), 3.40-3.33 (m, 1H), 2.72 (s, 3H).

Step F: 6-benzyloxy-4-bromo-2-methyl-1,3-benzothiazole: To a mixture of4-bromo-2-methyl-1,3-benzothiazol-6-ol (1.28 g, 5.24 mmol) and K₂CO₃(2.17 g, 15.72 mmol) in ACN (26.0 mL) was added BnBr (988 mg, 5.76 mmol,685 uL). The reaction mixture was stirred at 45° C. for 1 hour. Uponcompletion, the reaction mixture was filtered and the filtrate wasconcentrated. The residue was purified by column chromatography (PE/EA200/1 to 10/1) to give 6-benzyloxy-4-bromo-2-methyl-1,3-benzothiazole(1.10 g, 3.13 mmol, 59.7% yield, 95.0% purity) as a light yellow solid.ES+APCI MS m/z 336.2 [M+H]⁺.

Step G: benzyl4-[7-(6-benzyloxy-2-methyl-1,3-benzothiazol-4-yl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:Benzyl4-[2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(400 mg, 805 umol), 6-benzyloxy-4-bromo-2-methyl-1,3-benzothiazole (323mg, 967 umol), RuPhos (75.2 mg, 161 umol), Cs₂CO₃ (787 mg, 2.42 mmol)and Pd₂(dba)₃ (73.8 mg, 80.6 umol) in toluene (16 mL) was stirring at85° C. for 16 hours under N₂. Upon completion, the reaction mixture wasfiltered and the filtrate was concentrated. The residue was purified bycolumn chromatography over Al₂O₃ (PE/EA 10/1 to 0/1) to give benzyl4-[7-(6-benzyloxy-2-methyl-1,3-benzothiazol-4-yl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(340 mg, 408 umol, 50.7% yield, 90.0% purity) as a yellow oil. ES+APCIMS m/z 750.5[M+H]⁺.

Step H:2-methyl-4-[2-(3-morpholinopropoxy)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-1,3-benzothiazol-6-ol:To a solution of benzyl4-[7-(6-benzyloxy-2-methyl-1,3-benzothiazol-4-yl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(160 mg, 213 umol) in MeOH (4 mL) was added HCl/MeOH (4 M, 533 uL),followed by Pd(OH)₂/C (80 mg, 533 umol) under N₂. The suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred under H₂ (15 psi) at 40° C. for 8 hours. Upon completion, thereaction mixture was filtered and the filtrate was concentrated to give2-methyl-4-[2-(3-morpholinopropoxy)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-1,3-benzothiazol-6-ol(110 mg, 126 umol, 59.2% yield, 68.7% purity, 2 HCl) as a yellow solidwhich was used directly in the next step without further purification.ES+APCI MS m/z 526.2[M+H]⁺.

Step I:1-[4-[7-(6-hydroxy-2-methyl-1,3-benzothiazol-4-yl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a solution of2-methyl-4-[2-(3-morpholinopropoxy)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-1,3-benzothiazol-6-ol(110 mg, 184 umol, 2 HCl) and DIEA (143 mg, 1.10 mmol, 193 uL) in DCM(2.00 mL) was added prop-2-enoyl prop-2-enoate (18.5 mg, 147 umol)dropwise at −50° C. The mixture was stirred at −40-−20° C. for 30minutes. Upon completion, the mixture was quenched by MeOH (0.5 mL) andconcentrated under vacuum. The residue was diluted with water (2 mL) andextracted with DCM (3×6 mL). The organic layers were dried over Na₂SO₄and concentrated under vacuum. The residue was purified by columnchromatography over Al₂O₃ (DCM/MeOH 20/1 to 10/1), prep-HPLC (column:Gemini 150*25 5 u; mobile phase: [water (0.05% ammonia hydroxidev/v)-ACN]; B %: 21%-51%, 12 min) to give1-[4-[7-(6-hydroxy-2-methyl-1,3-benzothiazol-4-yl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(32.4 mg, 55.4 umol, 30.2% yield, 99.1% purity) as a yellow solid.ES+APCI MS m/z 580.4 [M+H]⁺.

Example 1671-(4-(7-(5-hydroxy-2-methyl-1H-indol-7-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: 2-bromo-4-methoxyaniline: At −10° C., to a solution of4-methoxyaniline (100 g, 812 mmol) in THF (3 L) was addedN-bromosuccinimide (152 g, 853 mmol) in three portions and the mixturewas stirred at the same temperature for 30 min. The mixture wasconcentrated under reduced pressure. The residue was purified by columnchromatography. (petroleum ether/ethyl acetate 15/1) to give2-bromo-4-methoxyaniline as red oil (30.58 g, 18.6% yield). ¹H NMR (400MHz, CDCl₃) δ 7.01 (d, J=2.4 Hz, 1H), 6.74-6.70 (m, 2H), 3.85-3.74 (m,2H), 3.73 (s, 3H).

Step B: 1-(2-amino-3-bromo-5-methoxyphenyl-2-chloropropan-1-one: To a 0°C. solution of 2-bromo-4-methoxy-aniline (15.0 g, 74.2 mmol) in1,1-dichloroethane (220 mL) was added boron trichloride (1.00 M, 89.1mL), 2-chloropropanenitrile (9.97 g, 111 mmol) and titaniumtetrachloride (16.9 g, 89.1 mmol). The mixture was heated at 85° C. for24 hours. The mixture was poured into ice and hydrochloric acid (20%,300 mL) at 0° C., concentrated and the residue was refluxed for 0.5hour. This mixture was basified at 0° C. with sodium hydroxide(saturated aqueous, 120 mL) until pH 4 was attained and then extractedwith ethyl acetate (300 mL×2). The combined organic extracts were washedwith brine (200 mL), dried with anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by columnchromatography (petroleum ether/ethyl acetate/dichloromethane 50/1/1),to give 1-(2-amino-3-bromo-5-methoxyphenyl)-2-chloropropan-1-one asyellow solid (18.7 g, 86.3% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.37 (d,J=2.8 Hz, 1H), 7.32 (d, J=2.8 Hz, 1H), 6.60 (brs, 2H), 5.25 (q, J=6.4Hz, 1H), 3.80 (s, 3H), 1.74 (d, J=6.4 Hz, 3H).

Step C: 7-bromo-5-methoxy-2-methyl-1H-indole: To a solution of1-(2-amino-3-bromo-5-methoxy-phenyl)-2-chloro-propan-1-one (18.7 g, 64.1mmol) in dioxane (500 mL) and H₂O (50 mL) was added NaBH₄ (2.67 g, 70.5mmol) and this mixture stirred at 100° C. for 15 hours. The mixture wascooled, diluted with hydrochloric acid (aq., 0.10 M, 100 mL) andextracted with dichloromethane (300 mL×2). The organics were washed withbrine (200 mL), dried with anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified by columnchromatography (petroleum ether/ethyl acetate 25/1) to give7-bromo-5-methoxy-2-methyl-1H-indole as yellow solid (7.01 g, 45.6%yield). ¹H NMR (400 MHz, CDCl₃) δ=7.91 (brs, 1H), 7.03-6.91 (m, 2H),6.23 (d, J=1.2 Hz, 1H), 3.84 (s, 3H), 2.46 (s, 3H).

Step D: tert-butyl4-(7-(5-methoxy-2-methyl-1H-indol-7-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:To a mixture of tert-butyl4-[2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(275 mg, 594 umol) and 7-bromo-5-methoxy-2-methyl-1H-indole (130 mg, 540umol) in 2-methyl-2-butanol (15.0 mL) was added ^(t)BuONa (104 mg, 1.08mmol) andchloro(2-dicyclohexylphosphino-2′,6′-di-^(i)-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II)methyl-t-butyl ether adduct (44.1 mg, 54.0 umol). This mixture stirredat 90° C. for 8 hours under a N₂ atmosphere. The mixture was filtered,concentrated under reduced pressure. The residue was purified byprep-TLC (dichloromethane/methanol 10/1), to give tert-butyl4-(7-(5-methoxy-2-methyl-1H-indol-7-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylateas yellow oil (131 mg, 36.8% yield). ES+APCI MS m/z 622.4 [M+H]⁺.

Step E:4-[3-[[7-(5-methoxy-2-methyl-1H-indol-7-yl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propyl]morpholine:To a 0° C. solution of tert-butyl4-[7-(5-methoxy-2-methyl-1H-indol-7-yl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(131 mg, 211 umol) in dichloromethane (10 mL) was added trifluoroaceticacid (2.00 mL) dropwise and the reaction stirred at 15° C. for 3 hours.The mixture was concentrated under reduced pressure, and the residue wasused in the next step without further purification. (126 mg crudeproduct). ES+APCI MS m/z 522.4 [M+H]⁺.

Step F:1-(4-(7-(5-methoxy-2-methyl-1H-indol-7-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one:To a −60° C. solution of4-[3-[[7-(5-methoxy-2-methyl-1H-indol-7-yl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propyl]morpholine(74 mg, 116 umol, trifluoroacetic acid salt) in dichloromethane (5 mL)was added diisopropylethylamine (45.1 mg, 349 umol, 60.8 uL) and themixture stirred at the same temperature for 10 min. The mixture wasquenched with citric acid (aq., 1.00 mL), extracted with dichloromethane(10 mL×2), washed with brine (15 mL), dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was purified byprep-TLC to give1-(4-(7-(5-methoxy-2-methyl-1H-indol-7-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-oneas yellow solid (31 mg, 39.2% yield). ES+APCI MS m/z 576.4 [M+H]⁺.

Step G:1-(4-(7-(5-hydroxy-2-methyl-1H-indol-7-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one:To a −78° C. solution of1-[4-[7-(5-methoxy-2-methyl-1H-indol-7-yl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(26 mg, 45.2 umol) in dichloromethane (5 mL) was added boron tribromide(56.6 mg, 226 umol, 21.8 uL). The reaction was allowed to warm to 0≤ C.and stirred for 12 hours. The mixture was neutralized withy NaHCO₃ (aq.,3 mL) and extracted with dichloromethane (5 mL 2), washed with brine (10mL), dried by anhydrous sodium sulfate, concentrated under vacuum. Theresidue was purified by prep-HPLC to give1-(4-(7-(5-hydroxy-2-methyl-1H-indol-7-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-oneas yellow solid (8.16 mg, 29.1% yield, 90.3% purity). ES+APCI MS m/z562.5[M+H]⁺.

Example 1681-(3-(hydroxymethyl)-4-(7-(3-hydroxynaphthalen-1-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: tert-butyl3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate: To asolution of tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (3.50g, 16.2 mmol) in THF (30 mL) was added NaH (3.24 g, 80.9 mmol, 60.0%purity) at 0° C. After stirring for 30 minutes, TBDPSCl (6.67 g, 24.3mmol, 6.23 mL) was added in one portion. The mixture was warmed to 10°C. and stirred for 12 hours under N₂ atmosphere. The reaction mixturewas quenched by addition water at 0° C., and then extracted with DCM(200 mL). The organic layer was dried with Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate 1/0 to 1/2) to givetert-butyl3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate (6.34g, 12.1 mmol, 74.8% yield, 86.8% purity) as a colorless oil. ES+APCI MSm/z 455.3 [M+H]⁺.

Step B:tert-butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate:A mixture of tert-butyl 3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate (7.25 g, 13.9 mmol),7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (3.89 g,13.2 mmol) and DIEA (4.27 g, 33.0 mmol, 5.77 mL) in DMSO (60 mL) wasstirred at 55° C. for 24 hours under N₂ atmosphere. The reaction mixturewas diluted with ethyl acetate (300 mL) and washed with brine (3×150mL). The organic layer was dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate 1/0 to 3/1) to givetert-butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate(4.50 g, 5.91 mmol, 44.7% yield, 93.5% purity) as a yellow solid.ES+APCI MS m/z 721.3 [M+H]⁺.

Step C:tert-butyl4-[7-benzyl-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate:A mixture of tert-butyl 4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate(2.00 g, 2.81 mmol), 3-morpholinopropan-1-ol (815 mg, 5.62 mmol),Pd(OAc)₂ (94.6 mg, 422 umol), BINAP (350 mg, 562 umol) and t-BuONa (674mg, 7.03 mmol) in toluene (30 mL) was degassed and purged with N₂ for 3times, and then the mixture was heated to 110° C. and stirred for 3hours under N₂ atmosphere. After completion, the reaction mixture wasfiltered and concentrated under reduced pressure. The residue waspurified by column chromatography (SiO₂, DCM/MeOH 70/1 to 20/1) to givetert-butyl4-[7-benzyl-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate(1.50 g, 1.69 mmol, 60.0% yield, 92.3% purity) as a yellow solid.ES+APCI MS m/z 821.4 [M+H]⁺.

Step D: tert-butyl3-[[tert-butyl(diphenyl)silyl]oxymethyl]-4-[2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of tert-butyl4-[7-benzyl-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate(1.50 g, 1.83 mmol) in MeOH (20 mL) was added Pd—C (10%, 1.5 g) underN₂. The suspension was degassed under vacuum and purged with H₂ severaltimes. The mixture was stirred under H₂ (50 psi) at 50° C. for 24 hours.The reaction mixture was filtered and concentrated under reducedpressure to give tert-butyl3-[[tert-butyl(diphenyl)silyl]oxymethyl]-4-[2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(988 mg, 1.21 mmol, 66.1% yield, 89.5% purity) as a colorless oil, whichwas used directly for next step without further purification. ES+APCI MSm/z 731.5 [M+H]⁺.

Step E:tert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate:A mixture of tert-butyl3-[[tert-butyl(diphenyl)silyl]oxymethyl]-4-[2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(731 mg, 1.00 mmol), 3-benzyloxy-1-bromo-naphthalene (783 mg, 2.50mmol),[2-(2-aminophenyl)phenyl]palladium(1+);dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane;methanesulfonate (169 mg, 200 umol), Cs₂CO₃ (815 mg, 2.50 mmol) intoluene (15 mL) was degassed and purged with N₂ 3 times, and then themixture was stirred at 60° C. for 24 hours under N₂ atmosphere. Thereaction mixture was filtered and concentrated under reduced pressure todryness and purified by column chromatography (SiO₂, DCM/MeOH=70/1 to30/1) to givetert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate(250 mg, 188 umol, 18.8% yield, 72.3% purity) as a yellow solid. ES+APCIMS m/z 963.4 [M+H]⁺.

Step F: tert-butyl3-[[tert-butyl(diphenyl)silyl]oxymethyl]-4-[7-(3-hydroxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of tert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate(250 mg, 188 umol) in MeOH (3 mL) was added 10% Pd/C (0.25 g) under N₂.The suspension was degassed under vacuum and purged with H₂ severaltimes. The mixture was stirred under H₂ (15 psi) at 50° C. for 3 hours.After completion, the reaction mixture was filtered and concentratedunder reduced pressure to dryness to give tert-butyl3-[[tert-butyl(diphenyl)silyl]oxymethyl]-4-[7-(3-hydroxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(180 mg, 128 umol, 68.1% yield, 62.0% purity) as a dark yellow solid,which was used directly for next step without further purification.ES+APCI MS m/z 873.4 [M+H]⁺.

Step G:4-[4-[2-(hydroxymethyl)piperazin-1-yl]-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol:A mixture of tert-butyl3-[[tert-butyl(diphenyl)silyl]oxymethyl]-4-[7-(3-hydroxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(130 mg, 149 umol), pyridine hydrofluoride (123 mg, 744 umol, 112 uL,60.0% purity) in THF (1.5 mL) was stirred at 25° C. for 12 hours underN₂ atmosphere. The reaction mixture was concentrated under reducedpressure to dryness. The residue was purified by reverse phase HPLC (TFAcondition; MeCN in H₂O; 0˜30%, flow rate; 40 mL/mins). The desiredfractions were concentrated under reduced pressure to give4-[4-[2-(hydroxymethyl)piperazin-1-yl]-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol(84 mg, 104 umol, 69.6% yield, 94.1% purity, 2 TFA) as a yellowsemisolid. ES+APCI MS m/z 535.3 [M+H]⁺.

Step H:1-[3-(hydroxymethyl)-4-[7-(3-hydroxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a mixture of4-[4-[2-(hydroxymethyl)piperazin-1-yl]-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol(84.0 mg, 114 umol, 2 TFA), DIEA (36.9 mg, 285 umol, 49.8 uL) in DCM (3mL) was added prop-2-enoyl prop-2-enoate (8.63 mg, 68.44 umol) drop wiseat −40° C., and then stirred at −40° C. for 0.5 hours under N₂atmosphere. The reaction mixture was quenched by addition MeOH (0.5 mL)and concentrated under reduced pressure to dryness. The residue waspurified by prep-HPLC (column: Venusil XBP C8 150*25*10 um; mobilephase: [water (0.225% Formic Acid)-ACN]; B %: 10%-40%, 10 min). Thedesired fractions were collected and lyophilized to dryness to give1-[3-(hydroxymethyl)-4-[7-(3-hydroxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(9.75 mg, 14.5 umol, 12.7% yield, 94.4% purity, Formic Acid Salt) as ayellow solid. ES+APCI MS m/z 589.3 [M+H]⁺.

Example 1691-[3-(hydroxymethyl)-4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: tert-butyl4-[7-benzyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate:To a mixture of tert-butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate(495 mg, 694 umol), [(2S)-1-methylpyrrolidin-2-yl]methanol (160 mg, 1.39mmol, 165 uL) and sodium tert-butoxide (200 mg, 2.08 mmol) in toluene(25 mL) was added BINAP (86.5 mg, 139 umol) and Pd₂(dba)₃ (63.6 mg, 69.5umol). The mixture was bubbled with nitrogen atmosphere and stirred at80° C. for 6 h. The reaction mixture was diluted with water (10 mL) andextracted with ethyl acetate (2×15 mL). The combined organic layers werewashed with water (2×30 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=30/1 to 1:1) to give tert-butyl4-[7-benzyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate(207 mg, 262 umol, 37.7% yield) as a yellow solid. ¹H NMR (400 MHz,chloroform-d) δ=7.62-7.53 (m, 4H), 7.43-7.28 (m, 1H), 4.42-4.29 (m, 1H),4.26-3.87 (m, 4H), 3.81 (br d, J=13.2 Hz, 2H), 3.75-3.60 (m, 4H), 3.44(dd, J=1.6, 17.2 Hz, 1H), 3.24-3.04 (m, 3H), 2.96 (br s, 1H), 2.75 (brs, 3H), 2.49 (s, 3H), 2.43-2.28 (m, 2H), 2.10-1.96 (m, 2H), 1.91-1.80(m, 1H), 1.80-1.67 (m, 2H), 1.43 (s, 9H), 1.02-0.89 (m, 9H).

Step B: tert-butyl 3-[[tert-butyl(diphenyl)silyl]oxymethyl]-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:NH₃ was bubbled in methanol (30 mL) at −40° C. for 30 minutes. To asolution of tert-butyl4-[7-benzyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate(530 mg, 670 umol) in above mixture was added dry 10% Pd/C (0.30 g)under N₂. The suspension was degassed under vacuum and purged with H₂several times. The mixture was stirred at 40° C. for 10 hours under 15psi of H₂. The reaction mixture was filtered and concentrated underreduced pressure to give tert-butyl3-[[tert-butyl(diphenyl)silyl]oxymethyl]-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(394 mg, 427 umol, 63.8% yield) as a yellow solid. ¹H NMR (400 MHz,chloroform-d) δ=7.57 (br t, J=6.0 Hz, 4H), 7.43-7.33 (m, 6H), 4.43 (brdd, J=5.2, 10.4 Hz, 1H), 4.32-4.00 (m, 4H), 3.99-3.89 (m, 2H), 3.88-3.65(m, 4H), 3.27-2.89 (m, 6H), 2.81 (br d, J=8.4 Hz, 2H), 2.56-2.50 (m,3H), 2.42 (br d, J=16.8 Hz, 2H), 2.13-2.03 (m, 1H), 1.88 (br d, J=6.8Hz, 1H), 1.79 (br d, J=5.2 Hz, 2H), 1.43 (s, 9H), 0.95 (br s, 9H).

Step C: tert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(2%)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate: A mixture of tert-butyl3-[[tert-butyl(diphenyl)silyl]oxymethyl]-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.16 g, 228 umol), 3-benzyloxy-1-bromo-naphthalene (143 mg, 457 umol),[2-(2-aminoethyl)phenyl]-chloro-palladium;dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (16.9 mg,22.8 umol) and t-BuONa (43.9 mg, 457 umol) in toluene (4 mL) was stirredat 70° C. for 12 hours under N₂. The mixture was diluted with water(5.00 mL) and extracted with ether acetate (3×10 mL). The combinedorganics were washed with saturated sodium chloride (10 mL), dried overNa₂SO₄, filtered and concentrated under vacuum. The residue was purifiedby reversed phase flash [water (formic acid, 0.1%)/acetonitrile] to givetert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(2S)-1-methylpyrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate(0.15 g, 157 umol, 68.9% yield) as a yellow solid. ES+APCI MS m/z 933.1[M+H]⁺.

Step D: tert-butyl3-[[tert-butyl(diphenyl)silyl]oxymethyl]-4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:NH₃ was bubbled into methanol (10 mL) at −78° C. for 30 minutes.tert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate(0.10 g, 107 umol) and dry 10% Pd/C (0.01 g) were added and the mixturewas stirred at 10° C. for 1 hour under 15 psi of H₂. The slurry wasfiltered through a pad of celite and the filtrate concentrated undervacuum to give tert-butyl3-[[tert-butyl(diphenyl)silyl]oxymethyl]-4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.09 g, crude) as a yellow oil and used into next step without furtherpurification. ES+APCI MS m/z 843.0 [M+H]⁺.

Step E:4-[4-[2-(hydroxymethyl)piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol:A mixture of tert-butyl3-[[tert-butyl(diphenyl)silyl]oxymethyl]-4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.04 g, crude) and pyridine; hydrofluoride (118 mg, 712 umol, 106 uL)in dichloromethane (2 mL) was stirred at 0° C. for 1 hour and stirred at10° C. for 12 hours. The pH of the mixture was adjusted to pH>7 byaddition of saturated sodium bicarbonate solution (3.00 mL) andconcentrated under vacuum. The residue was purified by columnchromatography (Al₂O₃, dichloromethane/methanol=5/1) to give4-[4-[2-(hydroxymethyl)piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol(0.04 g, crude) as a yellow solid. ES+APCI MS m/z 505.2 [M+H]⁺.

Step F:1-[3-(hydroxymethyl)-4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a solution of4-[4-[2-(hydroxymethyl)piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol(0.02 g, crude) and TEA (40.1 mg, 3% umol, 55.17 uL) in dichloromethane(2 mL) was added prop-2-enoyl prop-2-enoate (999 ug, 7.93 umol) at −40°C., then the mixture was stirred at −40° C. for 0.5 h. The mixture wasquenched by addition of methanol (0.10 mL) and concentrated undervacuum. The residue was purified by column chromatography (Al₂O₃,dichloromethane/methanol=5/1). The desired fractions were collected andconcentrated under vacuum. The residue was purified by prep-HPLC(column: Phenomenex Gemini 150*25 mm*10 um; mobile phase: [water (10 mMNH4HCO3)-ACN]; B %: 38%-68%, 3 min). The desired fractions werecollected and lyophilized to give1-[3-(hydroxymethyl)-4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(1.08 mg, 1.73 umol). ES+APCI MS m/z 559.5 [M+H]⁺.

Example 1702-(1-acryloyl-4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A:1-(tert-butyl)2-methyl4-(7-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1,2-dicarboxylate: To a solution of7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido [3,4-d] pyrimidine (5.00 g,17.0 mmol) and 1-tert-butyl 2-methylpiperazine-1,2-dicarboxylate (4.24g, 17.3 mmol) in DMSO (80 mL) was added DIEA (5.49, 42.5 mmol, 7.42 mL).After stirring at 55° C. for 12 hours, the mixture was diluted withethyl acetate (100 mL), washed with brine (3×150 mL), dried over Na₂SO₄,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography (SiO₂, PE/EA 3/1) to give 1-tert-butyl 2-methyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1,2-dicarboxylate (8.00 g, 15.9 mmol, 93.8%yield) as a yellow oil ES+APCI MS m/z 502.1 [M+H]⁺.

Step B: 1-(tert-butyl) 2-methyl4-(7-benzyl-2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl) piperazine-1,2-dicarboxylate: A mixture of1-tert-butyl 2-methyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1,2-dicarboxylate (8.00 g, 15.9 mmol),2-(dimethylamino)ethanol (2.84 g, 31.9 mmol, 3.19 mL), Cs₂CO₃ (13.0 g,39.8 mmol), Pd(OAc)₂ (537 mg, 2.39 mmol) and BINAP (1.98 g, 3.19 mmol)in toluene (30 mL) was stirred at 110° C. for 3 hours under nitrogen.The mixture was diluted with water (30 mL) and then extracted with ethylacetate (3×50 mL). The extracts were washed with brine (1×100 mL), driedover Na₂SO₄, filtered and concentrated under vacuum. The residue waspurified by reverse phase HPLC (TFA, 0.1%) to give 1-tert-butyl 2-methyl4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate(6.00 g, 10.8 mmol, 67.9% yield) as a yellow solid. ES+APCI MS m/z 555.3[M+H]⁺.

Step C: 1-tert-butyl 2-methyl4-[2-[2-(dimethylamino)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate:A mixture of 1-tert-butyl 2-methyl 4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate(6.00 g, 10.8 mmol) and 10% Pd/C (600 mg, 10.8 mmol) in MeOH (100 mL)was stirred at 40° C. for 12 hours under H₂ at 50 psi. The mixture wasfiltered and the filtrate was concentrated under vacuum to give1-tert-butyl 2-methyl4-[2-[2-(dimethylamino)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate(4.50 g, crude) was obtained as a yellow solid. ES+APCI MS m/z 465.3[M+H]⁺.

Step D: 1-tert-butyl 2-methyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate:A mixture of 1-tert-butyl 2-methyl4-[2-[2-(dimethylamino)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate(2.90 g, 6.24 mmol), 3-benzyloxy-1-bromo-naphthalene (2.54 g, 8.12mmol), Pd₂(dba)₃ (857 mg, 936 umol), RuPhos (728 mg, 1.56 mmol) andCs₂CO₃ (5.08 g, 15.6 mmol) in 1,4-dioxane (150 mL) was stirred at 85° C.for 5 hours under N₂. The mixture was diluted with water (100 mL),extracted with DCM (1×200 mL). The extracts were, washed with brine(1×300 mL), dried over Na₂SO₄, filtered and concentrated under vacuum.The residue was purified by reverse phase HPLC (TFA, 0.1%) to give1-tert-butyl 2-methyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate(3.50 g, 5.02 mmol, two steps 72.5% yield) as a brown solid. ES+APCI MSm/z 697.3 [M+H]⁺.

Step E: tert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(hydroxymethyl)piperazine-1-carboxylate:To a solution of 1-tert-butyl 2-methyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate(1.00 g, 1.44 mmol) in THF (10 mL) was added LiAlH₄ (219 mg, 5.76 mmol)in portions at −60° C. After stirring for 2 hours, the mixture wasquenched with saturated sodium sulfate solution (0.3 mL), filtered andthe filter cake washed with DCM (100 mL). The combined filtrate wasconcentrated under vacuum to give tert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(hydroxymethyl)piperazine-1-carboxylate (750 mg, 1.12mmol, 77.8% yield) as a yellow solid. ES+APCI MS m/z 669.3 [M+H]⁺.

Step F:2-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile:A mixture of tert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(hydroxymethyl)piperazine-1-carboxylate (100 mg, 149 umol), TBAI (11.1 mg, 29.9 umol),1-(p-tolylsulfonyl)imidazole (79.9 mg, 359 umol), NaCN (0.12 g, 2.45mmol), and TEA (37.8 mg, 374 umol, 51.8 uL) in DMF was stirred at 155°C. for 6 hours. The mixture was concentrated under vacuum, diluted withwater (1×5 mL) and then extracted with ethyl acetate (3×10 mL). Theextracts were washed with brine (1×20 mL), dried over Na₂SO₄, filteredand concentrated under vacuum. The residue was purified by prep-HPLCcolumn: Phenomenex Gemini C18 250*50 mm*10 um; mobile phase: [water(0.05% ammonia hydroxide v/v)-ACN]; B %: 50%-70%, 28 MIN) to give2-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(160 mg, 277 umol, 37.1% yield) as a yellow solid. ES+APCI MS m/z 578.5[M+H]⁺.

Step G:2-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile:To a solution of2-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(60 mg, 104 umol) and DIEA (67.1 mg, 519 umol, 90.7 uL) in DCM (2 mL)was added prop-2-enoyl prop-2-enoate (13.1 mg, 104 umol) at 0° C. Afterstirred at 10° C. for 4 hours, the mixture was quenched with MeOH (0.1mL), then concentrated under vacuum. The residue was purified by columnchromatography (SiO₂, DCM/MeOH 10/1) to give2-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile (40.0mg, 63.3 umol, 61.0% yield) as a yellow oil. ES+APCI MS m/z 632.3[M+H]⁺.

Step H:2-[4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile:To a solution of2-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(30 mg, 47.5 umol) in DCM (2 mL) was added BBr₃ (35.7 mg, 142 umol, 13.7uL) at −78° C. under 0.5 h. The mixture was warmed up to 0° C. andstirred for 2 hours. The mixture was concentrated under vacuum and thenquenched with saturated sodium bicarbonate solution at −78-0° C. Themixture was purified by column chromatography (Al₂O₃, DCM/MeOH=5/1),then further purified by prep-HPLC (column: Gemini 150*25 5 u; mobilephase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 30%-60%, 12 min).The desired fractions were collected and lyophilized to give2-[4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(810 ug, 1.46 umol, 3.07% yield. 97.5% purity) as a yellow solid.ES+APCI MS m/z 542.5 [M+H]⁺.

Example 1711-(4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(2-hydroxyethyl)piperazin-1-yl)prop-2-en-1-one

Step A: Ethyl 2-(3-oxopiperazin-2-yl)acetate: To a solution of diethyl(E)-but-2-enedioate (30.2 g, 175 mmol, 28.8 mL) in i-PrOH (300 mL) wasadded ethane-1,2-diamine (11.0 g, 183 mmol, 12.2 mL). After stirring at25° C. for 12 hours, the reaction mixture was concentrated under reducedpressure to dryness. The crude whit solid was washed with MTBE (500 mL)and dried under vacuum to give ethyl 2-(3-oxopiperazin-2-yl)acetate(26.0 g, 140 mmol, 79.6% yield, 100% purity) as a white solid. ¹H NMR(400 MHz, Chloroform-d) δ=6.55 (br s, 1H), 4.15 (q, J=6.8 Hz, 2H),3.80-3.72 (m, 1H), 3.47 (dt, J=4.8, 11.2 Hz, 1H), 3.36-3.22 (m, 1H),3.18-3.08 (m, 1H), 3.07-2.95 (m, 2H), 2.76-2.70 (m, 1H), 1.25 (t, J=7.2Hz, 3H).

Step B: Ethyl2-[1-[(4-methoxyphenyl)methyl]-3-oxo-piperazin-2-yl]acetate: To amixture of ethyl 2-(3-oxopiperazin-2-yl)acetate (23.6 g, 127 mmol) inmethanol (400 mL) was added 4-methoxybenzaldehyde (18.9 g, 139 mmol,16.9 mL) and CH₃COOH (15.2 g, 253 mmol, 14.5 mL) at 0° C. After stirringat 0° C. for 1 hour, the reaction mixture was cooled to −10° C. NaBH₃CN(23.9 g, 380 mmol) was added to the mixture in portions and the reactionmixture was warmed up to 15° C. and stirring for another 11 hours. Thereaction was quenched by adding water (400 ML) and extracted with DCM(2, 300 mL). The combined organic layers were dried over Na₂SO₄,filtered and concentrated. The residue was re-dissolved with ethylacetate (300 mL), then washed with 0.5 M HCl solution (2×200 mL). Theaqueous phase was adjusted to pH 7˜8 with Na₂CO₃ solid, then extractedwith DCM (2×300 mL). The combined organic layers were dried over Na₂SO₄,filtered and concentrated to give ethyl2-[1-[(4-methoxyphenyl)methyl]-3-oxo-piperazin-2-yl]acetate (27.2 g,87.6 mmol, 69.0% yield, 98.5% purity) as colorless oil. ES+APCI MS m/z307.1 [M+H]⁺.

Step C: 2-[1-[(4-methoxyphenyl)methyl]piperazin-2-yl]ethanol: To amixture of ethyl2-[1-[(4-methoxyphenyl)methyl]-3-oxo-piperazin-2-yl]acetate (27.2 g,88.8 mmol) in THF (500 mL) was added LiAlH₄ (10.1 g, 266 mmol) inportions at 0° C. After stirring at 0° C. for 1 hour, the reactionmixture was heated to 70° C. and stirred for 11 hours. After completion,the reaction was quenched with sat.Na₂SO₄ aqueous (40 mL), filtered andthen concentrated. The product2-[1-[(4-methoxyphenyl)methyl]piperazin-2-yl]ethanol (20 g, crude) wasobtained as yellow oil. ES+APCI MS m/z 251.1 [M+H]⁺.

Step D: tert-butyl-[2-[1-[(4-methoxyphenyl)methyl]piperazin-2-yl]ethoxy]-diphenyl-silane: To a mixture of2-[1-[(4-methoxyphenyl)methyl]piperazin-2-yl]ethanol (20 g, crude) inTHF (300 mL) was added NaH (15.9 g, 399 mmol, 60% purity) at 0° C. inportions, then a solution of TBDPSCl (65.9 g, 239 mmol, 61.6 mL) in THF(100 mL) was added. The mixture was warmed up to 15° C. and stirred fora further 12 hours. After completion, the reaction was poured into NH₄Clsolution (300 mL), and extracted with DCM (2×300 mL). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by column chromatography (SiO₂, Petroleumether:Ethyl acetate 3/1 to Dichloromethane/Methanol 10/1) to givetert-butyl-[2-[1-[(4-methoxyphenyl)methyl]piperazin-2-yl]ethoxy]-diphenyl-silane (29.5 g, 59.9 mmol, two steps35%, 99.2% purity) as yellow oil. ES+APCI MS m/z 489.4 [M+H]⁺.

Step E: tert-butyl3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-4-[(4-methoxyphenyl)methyl]piperazine-1-carboxylate:To a mixture of tert-butyl-[2-[1-[(4-methoxyphenyl)methyl]piperazin-2-yl]ethoxy]-diphenyl-silane (11.0 g, 22.5 mmol) inMeOH (200 mL) was added TEA (6.83 g, 67.5 mmol, 9.36 mL) and (Boc)₂O(9.82 g, 45.0 mmol, 10.3 mL). After stirring at 15° C. for 3 hours, thereaction was concentrated. The residue was purified by columnchromatography (SiO₂, Petroleum ether:Ethyl acetate 1/0 to 5/1) to givetert-butyl3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-4-[(4-methoxyphenyl)methyl]piperazine-1-carboxylate (11.0 g, 18.7 mmol, 82.9% yield, 100% purity)as colorless oil. ES+APCI MS m/z 589.4 [M+H]⁺.

Step F: tert-butyl 3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate: To a mixture of tert-butyl3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-4-[(4-methoxyphenyl)methyl]piperazine-1-carboxylate(9.00 g, 15.3 mmol) in MeOH (150 mL) was added 10% Pd/C (849 umol). Thesuspension was degassed under vacuum and purged with H₂ for three times.The mixture was stirred under H₂ (50 Psi) at 40° C. for 18 hours. Aftercompletion, the reaction mixture was filtered through a Celite plug andthe filtrate was concentrated. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate 10/1 to 3:1) to givetert-butyl 3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate (5.80 g, 12.2 mmol, 79.5% yield,98.2% purity) as colorless oil. ES+APCI MS m/z 469.4 [M+H]⁺.

Step G:2-[4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-1-[(4-methoxyphenyl)methyl]piperazin-2-yl]ethoxy-tert-butyl-diphenyl-silane:A mixture of 7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (4.00 g, 13.6 mmol),tert-butyl-[2-[1-[(4-methoxyphenyl)methyl]piperazin-2-yl]ethoxy]-diphenyl-silane (6.98 g, 14.3 mmol) and DIEA(4.39 g, 34.0 mmol, 5.93 mL) in DMSO (80 mL) was degassed and purgedwith N₂ for 3 times, and the mixture was heated to at 55° C. and stirredfor 12 hours under N₂ atmosphere. The reaction mixture was diluted withwater (300 mL) and extracted with ethyl acetate (3×200 mL) The combinedorganic layers were washed with brine (3×200 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to dryness. The residuewas purified by column chromatography (SiO₂, Petroleum ether/Ethylacetate 1/0 to 3/1) to give2-[4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-1-[(4-methoxyphenyl)methyl]piperazin-2-yl]ethoxy-tert-butyl-diphenyl-silane(9.00 g, 11.7 mmol, 86.0% yield, 97.0% purity) as a yellow oil. ES+APCIMS m/z 746.4 [M+H]⁺.

Step H:2-[[7-benzyl-4-[3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-4-[(4-methoxyphenyl)methyl]piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]-N,N-dimethyl-ethanamine:A mixture of 2-(dimethylamino)ethanol (2.39 g, 26.8 mmol, 2.69 mL),2-[4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-1-[(4-methoxyphenyl)methyl]piperazin-2-yl]ethoxy-tert-butyl-diphenyl-silane(8.00 g, 10.7 mmol), Pd(OAc)₂ (361 mg, 1.61 mmol), BINAP (1.34 g, 2.14mmol) and Cs₂CO₃ (8.73 g, 26.8 mmol) in toluene (100 mL) was degassedand purged with N₂ for 3 times. The mixture was heated to 110° C. andstirred for 3 hours under N₂ atmosphere. The reaction mixture wasfiltered and the filtrate was concentrated under reduced pressure todryness. The residue was purified by column chromatography (SiO₂,DCM/MeOH 50/1 to 10/1) to give2-[[7-benzyl-4-[3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-4-[(4-methoxyphenyl)methyl]piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]-N,N-dimethyl-ethanamine(6.50 g, crude) as a yellow semisolid. ES+APCI MS m/z 799.4 [M+H]⁺.

Step I: 2-[4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]ethanol:2-[4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]ethanol: A solution of2-[[7-benzyl-4-[3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-4-[(4-methoxyphenyl)methyl]piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]-N,N-dimethyl-ethanamine(6.50 g, crude) in TFA (80 mL) was stirred at 80° C. for 12 hours. Thereaction mixture was concentrated under reduced pressure to dryness andthe residue was re-dissolved into DCM (300 mL) and washed with water(200 mL). The water phase was collected and basified with saturatedNaHCO₃ aqueous to pH˜8 and then extracted with DCM (3×200 mL). Thecombined organic phase was dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give2-[4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]ethanol (3.00 g, crude) as a yellowsemisolid, which was used directly for next step without furtherpurification.

Step J:2-[[7-benzyl-4-[3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]-N,N-dimethyl-ethanamine:A solution of2-[4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]ethanol(3.0 g, crude) in THF (40 mL) was added NaH (1.36 g, 34.1 mmol, 60.0%purity) at 0° C. After stirring for 30 minutes, TBDPSCl (2.81 g, 10.2mmol, 2.63 mL) was added by portions. The mixture was warmed to 25° C.and stirred for another 2 hours under N₂ atmosphere. The reactionmixture was quenched by addition water (30 mL) at 0° C. and extractedinto ethyl acetate (3×100 mL). The combined organic layers were washedwith brine (3×100 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to dryness to give2-[[7-benzyl-4-[3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]-N,N-dimethyl-ethanamine(6.00 g, crude) as a yellow oil, which was used directly for next stepwithout further purification. ES+APCI MS m/z 679.4 [M+H]⁺.

Step K:tert-butyl4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate:A mixture of 2-[[7-benzyl-4-[3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]-N,N-dimethyl-ethanamine(6.0 g, crude), Boc₂O (18.5 g, 84.8 mmol, 19.5 mL) in MeOH (3 mL) wasdegassed and purged with N₂ for 3 times. The mixture was heated to 80°C. and stirred for 3 hours under N₂ atmosphere. The reaction mixture wasconcentrated under reduced pressure to dryness. The residue was purifiedby column chromatography (SiO₂, DCM/MeOH 1/0 to 10/1) to givetert-butyl4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate(3.10 g, 3.28 mmol, four steps 30.7% yield, 82.2% purity) as asemisolid. ES+APCI MS m/z 779.4 [M+H]⁺.

Step L:tert-butyl2-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-4-[2-[2-(dimethylamino)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution oftert-butyl4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate(3.10 g, 3.28 mmol, 82.2% purity) in MeOH (60 mL) was added Pd—C (10%, 2g) under N₂. The suspension was degassed under vacuum and purged with H₂for three times. The mixture was stirred under H₂ (50 psi) at 50° C. for36 hours. The reaction mixture was filtered and concentrated underreduced pressure to dryness to givetert-butyl2-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-4-[2-[2-(dimethylamino)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(2.20 g, 2.75 mmol, 83.8% yield, 86.0% purity) as a yellow solid, whichwas used directly for next step without further purification. ES+APCI MSm/z 689.4 [M+H]⁺.

Step M:tert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate:A mixture oftert-butyl2-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-4-[2-[2-(dimethylamino)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1.85 g, 2.69 mmol), 3-benzyloxy-1-bromo-naphthalene (1.09 g, 3.49mmol), Cs₂CO₃ (2.19 g, 6.71 mmol),[2-(2-aminophenyl)phenyl]palladium(1+);dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane;methanesulfonate (341 mg, 403 umol) in toluene (40 mL) was degassed andpurged with N₂ for 3 times, and the mixture was stirred at 65° C. for 10hours under N₂ atmosphere. After completion, the reaction mixture wasfiltered and concentrated under reduced pressure to dryness. The residuewas purified by column chromatography (SiO₂, DCM/MeOH 1/0 to 10/1) togivetert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate(1.85 g, 1.69 mmol, 63.2% yield, 84.3% purity) as a yellow solid.ES+APCI MS m/z 922.5 [M+H]⁺.

Step N:1-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazin-1-yl]prop-2-en-1-one:To a solution of tert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate(500 mg, 543 umol), 2,6-lutidine (700 mg, 6.51 mmol, 759 uL) in DCM (10mL) was added TMSOTf (724 mg, 3.26 mmol, 588 uL). After stirring at 40°C. for 2 hours under N₂ atmosphere, the reaction mixture was cooled to−40° C. and prop-2-enoyl prop-2-enoate (137 mg, 1.09 mmol) was addedportionwise. The reaction mixture was warmed to 25° C. and stirred foranother 12 hours under N₂ atmosphere. After completion, the reactionmixture was purified directly by column chromatography (SiO₂, DCM/MeOH30/1 to 10/1) to give1-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazin-1-yl]prop-2-en-1-one(256 mg, 226 umol, 41.6% yield, 77.2% purity) as a semisolid. ES+APCI MSm/z 875.5 [M+H]⁺.

Step O:1-[4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(2-hydroxyethyl)piperazin-1-yl]prop-2-en-1-one:To a solution of1-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazin-1-yl]prop-2-en-1-one(133 mg, 152 umol) in DCM (5.00 mL) was added BBr₃ (571 mg, 2.28 mmol,220 uL) dropwise at −40° C. The reaction mixture was warmed to 0° C. andstirred for 3 hours. The mixture was concentrated under reduced pressureto dryness. The crude material was washed with MTBE (25 mL) and thesolid was collected. The solid was washed with saturated NaHCO₃ solution(0.5 mL) to pH˜8 at 0° C. then dissolved in MeOH (3 mL). The mixture wasdirectly purified by prep-HPLC (column: Boston Green ODS 150*30 5 u;mobile phase: [water (0.225% Formic Acid)-ACN]; B %: 15%-39%, 10 min) togive1-[4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(2-hydroxyethyl)piperazin-1-yl]prop-2-en-1-one(16.7 mg, 28.2 umol, 18.5% yield, 99.9% purity, Formic Acid Salt) as ayellow solid. ES+APCI MS m/z 547.3 [M+H]⁺.

Example 1721-(4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-(2-hydroxyethyl)piperazin-1-yl)prop-2-en-1-one

Step A:tert-butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate:A mixture of 7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (3.04 g, 10.3 mmol),tert-butyl3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate (5.08 g, 10.8 mmol), DIEA (3.34 g, 25.8 mmol,4.51 mL) in DMSO (60 mL) was degassed and purged with N₂ for 3 times.The mixture heated to 55° C. and stirred for 16 hours under a N₂atmosphere. After cooling to room temperature, the reaction mixture wasdiluted with water (100 mL) and extracted with ethyl acetate (3×100 mL).The combined organic layers were washed with brine (3×100 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure todryness. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate 1/0 to 3/1) to givetert-butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate(3.50 g, 4.53 mmol, 43.9% yield, 94.0% purity) as a yellow semisolid.ES+APCI MS m/z 726.4 [M+H]⁺.

Step B: tert-butyl4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate:A mixture of 2-(dimethylamino)ethanol (1.07 g, 12.1 mmol, 1.21 mL),tert-butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate(3.50 g, 4.82 mmol), Pd(OAc)₂ (162 mg, 723 umol), BINAP (600 mg, 964umol) and Cs₂CO₃ (3.92 g, 12.1 mmol) in toluene (40 mL) was degassed andpurged with N₂ for 3 times. The mixture was heated to 110° C. withstirring for 3 hours under N₂ atmosphere. After cooling to the roomtemperature, the reaction mixture was filtered and concentrated underreduced pressure to dryness. The residue was purified by columnchromatography (SiO₂, DCM/MeOH=1/0 to 10/1) to give tert-butyl4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate(2.30 g, 2.57 mmol, 53.3% yield, 87.0% purity) as a yellow solid.ES+APCI MS m/z 779.5 [M+H]⁺.

Step C: tert-butyl3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-4-[2-[2-(dimethylamino)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of tert-butyl4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate (2.30 g, 2.95 mmol) in MeOH (40 mL) was addedPd—C (10%, 1.5 g) under N₂. The suspension was degassed under vacuum andpurged with H₂ several times. After stirring under H₂ (50 psi) at 50° C.for 36 hours, the reaction mixture was filtered and concentrated underreduced pressure to give tert-butyl3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-4-[2-[2-(dimethylamino)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1.58 g, 1.83 mmol, 61.9% yield, 79.6% purity) as a colorless oil, whichwas used directly for next step without further purification ES+APCI MSm/z 689.4 [M+H]⁺.

Step D:tert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate: A mixture of tert-butyl3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-4-[2-[2-(dimethylamino)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate (1.48 g, 2.15 mmol),3-benzyloxy-1-bromo-naphthalene (875 mg, 2.80 mmol), Cs₂CO₃ (1.75 g,5.38 mmol), [2-(2-aminophenyl)phenyl]palladium(1+);dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane;methanesulfonate (273 mg, 323 umol) in toluene (30 mL) was degassed andpurged with N₂ for 3 times, and then the mixture was stirred at 65° C.for 24 hours under N₂ atmosphere. The reaction mixture was filtered andconcentrated under reduced pressure to dryness. The residue was purifiedby column chromatography (Al₂O₃, DCM/MeOH=1/0 to 20/1) to givetert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate(1.20 g, 1.07 mmol, 49.7% yield, 82.0% purity) as a yellow solid.ES+APCI MS m/z 921.4 [M+H]⁺.

Step E: 2-[[7-(3-benzyloxy-1-naphthyl)-4-[2-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]-N,N-dimethyl-ethanamine: A mixture oftert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate(300 mg, 326 umol) and 2,6-lutidine (419 mg, 3.91 mmol, 455 uL) in DCM(10 mL) was added TMSOTf (434 mg, 1.95 mmol, 353 uL) portionwise at 0°C. The mixture was warmed to 10° C. and stirred for 12 hours under N₂atmosphere. The reaction mixture was purified directly by columnchromatography (Al₂O₃, DCM/MeOH 1/0 to 50/1) to give2-[[7-(3-benzyloxy-1-naphthyl)-4-[2-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]-N,N-dimethyl-ethanamine(210 mg, 229 umol, 70.3% yield, 89.5% purity) as a yellow semi-solid.ES+APCI MS m/z 821.5 [M+H]⁺.

Step F:1-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazin-1-yl]prop-2-en-1-one: To a mixture of2-[[7-(3-benzyloxy-1-naphthyl)-4-[2-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]-N,N-dimethyl-ethanamine (210 mg, 256 umol) and DIEA(49.6 mg, 384 umol, 67.0 uL) in DCM (10 mL) was added prop-2-enoylprop-2-enoate (33.9 mg, 269 umol) portionwise at −40° C. under nitrogenatmosphere. After stirring for 30 minutes at the same temperature, thereaction mixture was purified directly by column chromatography (Al₂O₃,DCM/MeOH 1/0 to 50/1) to give1-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazin-1-yl]prop-2-en-1-one(221 mg, 214 umol, 83.6% yield, 84.7% purity) as a slight yellowsemi-solid. ES+APCI MS m/z 875.4 [M+H]⁺.

Step G:1-[4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-(2-hydroxyethyl)piperazin-1-yl]prop-2-en-1-one:A mixture of 1-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazin-1-yl]prop-2-en-1-one(221 mg, 253 umol) in DCM (10 mL) was added BBr₃ (949 mg, 3.79 mmol, 365uL) at −40° C. The mixture was stirred at 0° C. for 3 hours under N₂atmosphere. The reaction mixture was concentrated under reduced pressureto dryness. The crude pdt was washed with MTBE (25 mL), saturated NaHCO₃solution (0.5 mL) to pH˜8 at 0° C. and dissolved in MeOH (3 mL). Theresulting solution was purified by prep-HPLC (column: Boston Green ODS150*30 5 u; mobile phase: [water (0.225% Formic Acid)-ACN]; B %:11%-41%, 10 min) to give1-[4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-(2-hydroxyethyl)piperazin-1-yl]prop-2-en-1-one(26.7 mg, 44.0 umol, 17.4% yield, 97.8% purity, Formic Acid Salt) as ayellow solid. ES+APCI MS m/z 547.3 [M+H]⁺.

Example 1731-(4-(7-(3-hydroxy-2-methylnaphthalen-1-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

1-(4-(7-(3-hydroxy-2-methylnaphthalen-1-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-onewas prepared according to the procedure for Example 1651-[4-[7-(2-fluoro-3-hydroxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-onesubstituting (3-methoxy-2-methyl-1l-naphthyl) trifluoromethanesulfonatefor (2-fluoro-3-methoxy-1-naphthyl) trifluoromethanesulfonate in step Fto give the desired product1-(4-(7-(3-hydroxy-2-methylnaphthalen-1-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-oneas yellow solid (10.4 mg, 13.1% yield, 98.1% purity). ES+APCI MS m/z573.5 [M+H]⁺.

Example 174(R)-1-(4-(2-((5,5-dimethylpyrrolidin-2-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: tert-Butyl(5R)-5-(hydroxymethyl)-2,2-dimethyl-pyrrolidine-1-carboxylate: To asolution of(2R)-1-tert-butoxycarbonyl-5,5-dimethyl-pyrrolidine-2-carboxylic acid(500 mg, 2.06 mmol) in anhydrous THF (4 mL) was added BH₃-Me₂S (2 M,1.23 mL) dropwise at 15° C. The reaction was heated at 50° C. for 5minutes. After Cooling in an ice-bath, to the mixture was added Methanol(20 mL). The reaction mixture was concentrated under reduced pressure at25° C. tert-Butyl(5R)-5-(hydroxymethyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (400 mg,1.74 mmol, 84.9% yield) was obtained as a white solid.

¹H NMR (400 MHz, methanol-d₄) δ=3.97-3.81 (m, 1H), 3.62 (dd, J=3.6, 10.8Hz, 1H), 3.45-3.33 (m, 1H), 2.02-1.79 (m, 3H), 1.79-1.67 (m, 1H),1.49-1.41 (m, 12H), 1.32 (s, 3H).

Step B: Benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(2R)-1-tert-butoxycarbonyl-5,5-dimethyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of tert-butyl(5R)-5-(hydroxymethyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (212 mg,926 umol) and benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(300 mg, 463 umol,) in THF (10 mL) was added t-BuONa (133 mg, 1.39mmol). After stirring at 15° C. for 1 hour, the reaction mixture waspoured into H₂O (20 mL) and extracted with ethyl acetate (20 mL×3). Theorganic phase was washed with brine (20 mL), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The residue was purified byreversed phase flash [water (0.1% formic acid)/acetonitrile]. Thedesired fractions were collected and concentrated under vacuum. Compoundbenzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(2R)-1-tert-butoxycarbonyl-5,5-dimethyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(110 mg, 129 umol, 28.1% yield, 96% purity) was obtained as a yellowsolid. ES+APCI MS m/z 813.5 [M+H]⁺.

Step C: tert-butyl(5R)-5-[[7-(3-hydroxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]-2,2-dimethyl-pyrrolidine-1-carboxylate:NH₃ was bubbled into MeOH (30 mL) at −40° C. for 30 minutes. To asolution of benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(2R)-1-tert-butoxycarbonyl-5,5-dimethyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 246 umol) in above the mixture (NH₃/MeOH) was added dry Pd—C(10%, 100 mg) under N₂. The suspension was degassed under vacuum andpurged with H₂ several times. The mixture was stirred under H₂ (15 psi)at 15° C. for 1 hour. The catalyst was filtered off and the filtrate wasconcentrated to give the product tert-butyl(5R)-5-[[7-(3-hydroxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]-2,2-dimethyl-pyrrolidine-1-carboxylate(150 mg, 244 umol, 99.4% yield, 96% purity) as a yellow solid anddirectly used next step without purification. ES+APCI MS m/z 589.3[M+H]⁺.

Step D: tert-Butyl(5R)-5-[[7-(3-hydroxy-1-naphthyl)-4-(4-prop-2-enoylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]-2,2-dimethyl-pyrrolidine-1-carboxylate:To a mixture of tert-butyl(5R)-5-[[7-(3-hydroxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]-2,2-dimethyl-pyrrolidine-1-carboxylate(130 mg, 221 umol) and DIEA (285 mg, 2.21 mmol, 385 uL) indichloromethane (3 mL) was added a solution of prop-2-enoylprop-2-enoate (22.3 mg, 176 umol) in dichloromethane (1 mL) at −40° C.under nitrogen atmosphere. The mixture was stirred at −40° C. for 1hour. The reaction was quenched by addition of saturated NaHCO₃ (2 mL)aqueous solution. Then the mixture was poured into water (20 mL) andextracted with dichloromethane (20 mL×2). The combined organics wasdried over sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by column chromatography (SiO₂,dichloromethane/methanol=1/0 to 10/1). tert-Butyl(5R)-5-[[7-(3-hydroxy-1-naphthyl)-4-(4-prop-2-enoylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]-2,2-dimethyl-pyrrolidine-1-carboxylate(140 mg, 217 umol, 98.6% yield) was obtained as a brown oil. ES+APCI MSm/z 643.6 [M+H]⁺.

Step E:1-[4-[2-[[(2R)-5,5-dimethylpyrrolidin-2-yl]methoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a solution of tert-butyl(5R)-5-[[7-(3-hydroxy-1-naphthyl)-4-(4-prop-2-enoylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]-2,2-dimethyl-pyrrolidine-1-carboxylate(120 mg, 187 umol) in dichloromethane (200 uL) was added TFA (212 mg,1.87 mmol, 138 uL). The mixture was stirred at 15° C. for 1 hour. Thereaction mixture was concentrated under vacuum, then diluted withdichloromethane (5 mL) and adjusted PH=7 by addition saturated NaHCO₃aqueous solution. The mixture was extracted with dichloromethane (10mL×3). The combined organic phase was dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified byprep-HPLC (column: Phenomenex Gemini 150*25 mm*10 um; mobile phase:[water (0.05% ammonia hydroxide v/v)-ACN]; B %: 45%-75%, 12 min),1-[4-[2-[[(2R)-5,5-dimethylpyrrolidin-2-yl]methoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(30 mg, 53.6 umol, 28.7% yield, 97% purity) was obtained as yellow solidby lyophilization. ES+APCI MS m/z 543.5 [M+H]⁺.

Example 175(S)-1-(4-(7-(3-hydroxy-2-methylnaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

(S)-1-(4-(7-(3-hydroxy-2-methylnaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-onewas synthesized according to the procedure for Example 165 substitutingtert-butyl4-[2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylatefor tert-butyl4-[7-(2-fluoro-3-methoxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylateand (2-fluoro-3-methoxy-1-naphthyl) trifluoromethanesulfonate for(3-methoxy-2-methyl-1-naphthyl) trifluoromethanesulfonate in Step F, togive1-[4-[7-(3-hydroxy-2-methy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(10.2 mg, 17.3 umol, 21.4% yield, 100% purity, Formic Acid Salt) as awhite solid. ES+APCI MS m/z 543.4 [M+H]⁺.

Example 1762-[(2S)-4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: tert-butyl(3aR)-1-oxo-3a,4,6,7-tetrahydro-3H-oxathiazolo[3,4-a]pyrazine-5-carboxylate:To a solution of imidazole (15.7 g, 231 mmol) in DCM (100 mL) was addedSOCl₂ (8.25 g, 69.4 mmol, 5.03 mL) at 0° C. The reaction mixture wasstirred at 15° C. for 1 hour. To the mixture was added tert-butyl(3R)-3-(hydroxymethyl)piperazine-1-carboxylate (5 g, 23.1 mmol) in DCM(100 mL) at −70° C. The reaction mixture was stirred at 15° C. for 12hour. Upon completion the reaction mixture was quenched by saturatedNH₄Cl (100 mL) and separated, the aqueous layer was extracted with DCM(40 mL). The combined organic layers were washed with brine (20 mL),dried over Na₂SO₄, filtered and concentrated under vacuum to givetert-butyl(3aR)-1-oxo-3a,4,6,7-tetrahydro-3H-oxathiazolo[3,4-a]pyrazine-5-carboxylate(5.8 g, 22.1 mmol, 95.6% yield) as a brown solid.

Step B: tert-butyl(3aR)-1,1-dioxo-3a,4,6,7-tetrahydro-3H-oxathiazolo[3,4-a]pyrazine-5-carboxylate:To a solution of tart-butyl(3aR)-1-oxo-3a,4,6,7-tetrahydro-3H-oxathiazolo[3,4-a]pyrazine-5-carboxylate(7.5 g, 28.6 mmol) in MeCN (225 mL) was added NaIO₄ (7.95 g, 37.2 mmol,2.06 mL) in water (75 mL) followed by RuCl₃·H₂O (129 mg, 572 umol) at 0°C. The reaction mixture was stirred at 15° C. for 0.5 hour. Uponcompletion, the reaction mixture was quenched with saturated NH₄Cl (10mL) and extracted with EtOAc (20 mL). The organic layer was washed withbrine (10 mL), dried over Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by silica gel chromatography(PE:EtOAc=3:1 to 1:1) to give tert-butyl(3aR)-1,1-dioxo-3a,4,6,7-tetrahydro-3H-oxathiazolo[3,4-a]pyrazine-5-carboxylate(7 g, 25.2 mmol, 88.0% yield) as a white solid. ¹H NMR (400 MHz,CHLOROFORM-d) δ=4.64 (dd, J=6.4, 8.0 Hz, 1H), 4.36-3.94 (m, 3H), 3.64(ddt, J=3.6, 6.0, 9.2 Hz, 1H), 3.46 (br d, J=11.6 Hz, 1H), 3.13 (br s,1H), 2.96 (dt, J=3.2, 11.2 Hz, 2H), 1.48 (s, 9H)

Step C: tert-butyl (3S)-3-(cyanomethyl)piperazine-1-carboxylate: To asolution of tert-butyl(3aR)-1,1-dioxo-3a,4,6,7-tetrahydro-3H-oxathiazolo[3,4-a]pyrazine-5-carboxylate(5 g, 18.0 mmol) in DMF (100 mL) was added KCN (1.04 g, 16.0 mmol,684.94 uL). The reaction mixture was heated to 50° C. for 16 hours. Uponcompletion, the reaction mixture was quenched by HCl (2 M, 50 mL) andstirred at 15° C. for 1 h. The mixture was basidified by NaOH (40%, 10mL) and extracted with EtOAc (3×100 mL). The organic layer was driedover Na₂SO₄ and concentrated under vacuum. The residue was purified bysilica gel chromatography (PE:EtOAc=3:1 to 0:1 then EtOAc:MeOH=100:1 to10:1) to give tert-butyl (3S)-3-(cyanomethyl)piperazine-1-carboxylate(1.1 g, 4.88 mmol, 27.2% yield) as a brown oil. ¹H NMR (400 MHz,CHLOROFORM-d) δ=4.05-3.71 (m, 2H), 3.08-2.88 (m, 3H), 2.84-2.62 (m, 2H),2.56-2.37 (m, 2H), 1.47 (s, 9H).

Step D: 2-[(2S)-piperazin-2-yl]acetonitrile: A reaction mixture oftert-butyl (3S)-3-(cyanomethyl)piperazine-1-carboxylate (850 mg, 3.77mmol) and HCl/dioxane (4 M, 20 mL) was stirred at 15° C. for 1 hour.Upon completion, the solvent was removed under vacuum to give2-[(2S)-piperazin-2-yl]acetonitrile (740 mg, 3.74 mmol, 99.0% yield,2HCl) as a white solid. ¹H NMR (400 MHz, METHANOL-d₄) δ=4.04-3.90 (m,1H), 3.81-3.70 (m, 2H), 3.69-3.61 (m, 2H), 3.53-3.36 (m, 2H), 3.13 (d,J=6.4 Hz, 2H).

Step E:2-[(2S)-4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl]acetonitrile:To a mixture of7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (1.3 g,4.42 mmol) and 2-[(2S)-piperazin-2-yl]acetonitrile (1.17 g, 5.91 mmol,2HCl) in dioxane (25 mL) was added DIEA (2.86 g, 22.1 mmol, 3.85 mL).The reaction mixture was stirred at 50° C. for 12 hours. Uponcompletion, the reaction mixture was diluted with water (50 mL) andextracted with EtOAc (3×80 mL). The combined organic layers were washedwith brine (30 mL), dried over Na₂SO₄ and concentrated under vacuum togive2-[(2S)-4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl]acetonitrile(1.69 g, 4.41 mmol, 1000 yield) as a brown solid.

Step F: tert-butyl(2S)-4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:A reaction mixture of2-[(2S)-4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl]acetonitrile(1.69 g, 4.41 mmol) and (Boc)₂O (10.3 g, 47.2 mmol, 10.8 mL) was heatedto 50° C. for 2 hours. Upon completion, the reaction mixture waspurified by silica gel chromatography (PE:EtOAc=10:1 to 1:1) to givetert-butyl(2S)-4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(1.1 g, 2.12 mmol, 48.0% yield, 93% purity) as brown solid. ES+APCI MSm/z 483.4 [M+H]⁺.

Step G: tert-butyl(2S)-4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate:To a solution of 2-(dimethylamino)ethanol (415 mg, 4.66 mmol, 468 uL) inTHF (20 mL) was added NaH (149 mg, 3.73 mmol, 60% purity) 0° C. Thereaction mixture was stirred at 0° C. for 0.5 h. To the mixture wasadded tert-butyl(2S)-4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(900 mg, 1.86 mmol). The reaction mixture was stirred at 70° C. for 12hours at sealed tube under N₂. Upon completion, the reaction mixture wasquenched by water (10 mL) and extracted with EtOAc (3% 40 mL). Thecombined organic layers were treated with activated carbon and filtered.The filtrate was concentrated under vacuum to give tert-butyl(2S)-4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(600 mg, 1.12 mmol, 60.1% yield) as a brown solid.

Step H: tert-butyl(2S)-2-(cyanomethyl)-4-[2-[2-(dimethylamino)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:NH₃ was bubbled into MeOH (20 mL) for 5 min. To the solution was addedtert-butyl(2S)-4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(600 mg, 1.12 mmol) and 10% Pd/C (200 mg). The suspension was degassedunder vacuum and purged with H₂ several times. The mixture was stirredunder H₂ (15 psi) at 40° C. for 16 hours. Upon completion, the mixturewas filtered and the filter cake was washed with MeOH (3×30 mL). Thefiltrate was concentrated under vacuum. The residue was purified byprep-HPLC (column: Phenomenex luna (2) C18 250*50 10u; mobile phase:[water (0.225% Formic Acid)-ACN]; B %: %-%, 30 MIN; 60% min) to giveter-butyl(2S)-2-(cyanomethyl)-4-[2-[2-(dimethylamino)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(167 mg, 331 umol, 29.6% yield, 88.3% purity) as a colorless oil.ES+APCI MS m/z 446.3 [M+H]⁺.

Step I: tert-butyl(2S)-2-(cyanomethyl)-4-[2-[2-(dimethylamino)ethoxy]-7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of tert-butyl(2S)-2-(cyanomethyl)-4-[2-[2-(dimethylamino)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(180 mg, 404 umol), (4-bromo-2-naphthyl) 2,2-dimethylpropanoate (248 mg,808 umol) and Cs₂CO₃ (395 mg, 1.21 mmol) in toluene (6 mL) was addedXPHOS Palladacycle Gen 3 (34.20 mg, 40.4 umol). The reaction mixture wasstirred at 70° C. for 4 hours under N₂. Upon completion, the reactionmixture was purified by silica gel chromatography (PE:EA=5:1 to 0.1) togive tert-butyl(2S)-2-(cyanomethyl)-4-[2-[2-(dimethylamino)ethoxy]-7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 272 umol, 67.3% yield, 91.3% purity) as a brown solid. ES+APCIMS m/z 672.0 [M+H]⁺.

Step J:[4-[4-[(3S)-3-(cyanomethyl)piperazin-1-yl]-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate: To a solution of tert-butyl(2S)-2-(cyanomethyl)-4-[2-[2-(dimethylamino)ethoxy]-7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 298 umol) in DCM (0.3 mL) was added TFA (420 mg, 3.68 mmol, 273uL). The reaction mixture was stirred at 15° C. for 1 hour. Uponcompletion, the reaction mixture was concentrated under vacuum to give[4-[4-[(3S)-3-(cyanomethyl)piperazin-1-yl]-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (238 mg, 298 umol, 99.9% yield, 2 TFA) as a brownoil.

Step K:[4-[4-[(3S)-3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate: To a solution of[4-[4-[(3S)-3-(cyanomethyl)piperazin-1-yl]-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (238 mg, 298 umol, 2 TFA) and DIEA (308 mg, 2.38mmol, 415 uL) in DCM (5 mL) was added prop-2-enoyl prop-2-enoate (56.3mg, 446 umol) at 0° C. The reaction mixture was stirred at 15° C. for 1hour. Upon completion, the reaction mixture was quenched with a drop ofwater. The mixture (was purified by silica gel chromatography(PE:EtOAc=1:1 to 0:1 then EtOAc:MeOH=50:1 to 3:1) to give[4-[4-[(3S)-3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl] 2,2-dimethylpropanoate (300 mg, crude) as abrown oil. ES+APCI MS m/z 626.4 [M+H]⁺.

Step L:2-[(2S)-4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile:To a solution of[4-[4-[(3S)-3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (300 mg, 479 umol) in THF (3 mL) was added NaOH(2 M, 3 mL) in water. The reaction mixture was stirred at 15° C. for 8hours. Upon completion, the reaction mixture was acidified by 0.5 mL offormic acid (20% in water) to PH=7 and extracted with DCM (5×10 mL). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated under vacuum.

The residue was purified by prep-HPLC (column: Boston Green ODS 150*30 5u; mobile phase: [water (0.225% Formic Acid)-ACN]; B %: 25%-49%, 10 min)to give2-[(2S)-4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(18.3 mg, 30.2 umol, two steps 10:1% yield, 96.7% purity, Formic AcidSalt) as a yellow solid. ES+APCI MS m/z 542.5 [M+H]⁺.

Example 1772-[4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: tert-butyl2-(cyanomethyl)-4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of tert-butyl2-(cyanomethyl)-4-[2-methylsulfinyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(300 mg, 549 umol) and [(3R)-1-methylpyrrolidin-3-yl]methanol (126 mg,1.10 mmol) in toluene (6 mL) was added t-BuONa (79.1 mg, 823 umol) at18° C. and the reaction mixture stirred at 18° C. for 0.5 hour. To themixture was then added EtOAc (20 mL) and water (15 mL), then extractedwith EtOAc (3×20 mL). The combined organic layers were washed with brine(20 mL). The combined organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by reversed phase flash column (ACN/Water (0.1% FormicAcid)=42%) to give tert-butyl2-(cyanomethyl)-4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 331 umol, 60.4% yield, 99.0% purity) as yellow solid. ES+APCIMS m/z 598.3 [M+H]⁺.

Step B:2-[4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile:A mixture of tert-butyl2-(cyanomethyl)-4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 334 umol) and TFA (763 mg, 6.69 mmol, 495 uL) was stirred at18° C. for 1 hour. The reaction mixture was concentrated under vacuum togive2-[4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(250 mg, crude, 2 TFA) as brown oil.

Step C:2-[4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile:To a solution of2-[4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(250 mg, 344 umol, 2 TFA) and DIEA (356 mg, 2.76 mmol, 480 uL) in DCM (5mL) was added prop-2-enoyl prop-2-enoate (65.2 mg, 517 umol) at 0° C.and the mixture was stirred at 18° C. for 1.5 hours. The reactionmixture was quenched with water (3 mL) and then extracted with DCM (3×6mL). The combined organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by prep-HPLC (column: Phenomenex Gemini 150*25 mm*10 um; mobilephase: [water (10 mM NH4HCO3)-ACN]; B %: 30%-60%, 3 min) to give2-[4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(9.98 mg, 17.0 umol, 4.94% yield, 94.1% purity) as white solid. ES+APCIMS m/z 552.5[M+H]⁺.

Example 1782-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A:7-benzyl-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-ol: Asuspension of MeOH (1000 mL) and Na (22.0 g, 957 mmol, 22.7 mL) wasstirred for 30 min. To this mixture was added ethyl1-benzyl-3-oxo-piperidine-4-carboxylate (50 g, 191 mmol and2-methylisothiourea (47.9 g, 344 mmol, 0.5H₂SO₄) at 15° C. The reactionmixture was stirred at 15° C. for 30 hours. The reaction mixtureacidified by HCl (2 M) (300 mL) until pH=6 and concentrated underreduced pressure. The residue was suspended in 200 mL of water andstirred rapidly. The suspension was filtered and the white solidcollected and washed with ethyl acetate.7-benzyl-2-methylsulfanyl-6,8-dihydro-5H-pyrido-[3,4-d]pyrimidin-4-ol(68 g, 151 mmol, 79.1% yield, 64.0% purity) was obtained as a whitesolid.

Step B:7-benzyl-4-chloro-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine:To a solution of7-benzyl-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-ol (50g, 174 mmol) in CHCl₃ (1000 mL) was added POCl₃ (166 g, 1.08 mol, 100mL) and the mixture stirred at 80° C. for 13 hours. Upon completion, thereaction mixture was concentrated under vacuum. The residue was dilutedwith EtOAc (500 mL) and basified using saturated Na₂CO₃ (800 mL) toPH=7. The mixture was extracted with ethyl acetate (3×400 mL). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (PE:EA from 100:1 to 80:1) to give7-benzyl-4-chloro-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(21.7 g, 67.4 mmol, 38.7% yield, 95.0% purity) as brown oil. ES+APCI MSm/z 306.1 [M+H]⁺.

Step C: tert-butyl4(7-benzyl-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:To a solution of7-benzyl-4-chloro-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(2.6 g, 8.50 mmol) and 2-piperazin-2-ylacetonitrile (1.68 g, 8.50 mmol,2HCl) in DMSO (52 mL) was added DIEA (5.49 g, 42.5 mmol, 7.40 mL). Themixture was warmed to 80° C. and stirred at 80° C. for 6 hours. To themixture was added (Boc)₂O (18.5 g, 85.0 mmol, 19.5 mL) and the mixturestirred at 80° C. for 1 hour. Water (150 mL) was added and the mixturewas extracted with ethyl acetate (3×200 mL). The combined organic phasewas washed with brine (200 mL), dried with anhydrous Na₂SO₄, filteredand concentrated in vacuum. The residue was purified by silica gelchromatography (PE:EA from 10:1 to 0:1) to give tert-butyl4-(7-benzyl-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(2.74 g, 5.26 mmol, 61.9% yield, 95.0% purity) as brown solid ES+APCI MSm/z 495.4 [M+H]⁺.

Step D: tert-butyl2-(cyanomethyl)-4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:To a solution of tert-butyl4-(7-benzyl-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(2.51 g, 5.07 mmol) and DIEA (1.97 g, 15.2 mmol, 2.65 mL) in DCE (50 mL)was added 1-chloroethyl carbonochloridate (1.81 g, 12.7 mmol) at 0° C.,and the mixture stirred at 15° C. for 3 hours. The reaction mixture wasconcentrated under vacuum. The residue was dissolved in MeOH (50 mL) andthe reaction mixture was stirred at 70° C. for 1.5 hours. The mixturewas concentrated under vacuum. The residue was purified by prep-HPLC(column: Phenomenex Synergi Max-RP 250*50 mm*10 um; mobile phase: [water(0.225% FA)-ACN]; B %: 23%-48%, 30; 50% min) to give tert-butyl2-(cyanomethyl)-4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(1.13 g, 2.51 mmol, 49.5% yield, 90.0% purity) as pink solid. ES+APCI MSm/z 405.3 [M+H]⁺.

Step E: tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of tert-butyl2-(cyanomethyl)-4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(730 mg, 1.80 mmol), (4-bromo-2-naphthyl) 2,2-dimethylpropanoate (832mg, 2.71 mmol) and Cs₂CO₃ (1.76 g, 5.41 mmol) in toluene (18 mL) wasadded[2-(2-aminophenyl)phenyl]palladium(1+);dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane-methanesulfonate(153 mg, 180 umol), the suspension was degassed under vacuum and purgedwith N₂ several times. The reaction mixture was stirred at 70° C. for 4hours. Upon completion, water (20 mL) was added to the mixture. Theresulting mixture was extracted with EtOAc (4×20 mL). The combinedorganic layers were washed with brine (40 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure The residue waspurified by silica gel chromatography (PE:EtOAc from 30:1 to 0:1) togive tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(740 mg, 1.15 mmol, 63.7% yield, 98.0% purity) as brown solid. ES+APCIMS m/z 631.5[M+H]⁺.

Step F: tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(100 mg, 158 umol) in DCM (2 mL) was added m-CPBA (32.2 mg, 158 umol,85.0% purity) at 0° C. and the mixture stirred at 0° C. for 1 hours. Thereaction mixture was quenched by saturated Na₂S₂O₃ (4 mL) at 0° C. andseparated, then diluted with water (10 mL) and extracted with ethylacetate (10 mL). The combined organic layers were washed with brine (20mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by silicagel chromatography (PE:EA from 10:1 to 0:1) to give tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(90 mg, 125 umol, 79.0% yield, 90.0% purity) as brown solid. ES+APCI MSm/z 647.5[M+H]⁺.

Step G: tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(560 mg, 866 umol), [(2R)-1-methylpyrrolidin-2-yl]methanol (199 mg, 1.73mmol) in toluene (10 mL) was added t-BuONa (125 mg, 1.30 mmol) at 0° C.and the mixture was stirred at 0° C. for 0.5 hour. The mixture waspartitioned between EtOAc (20 mL) and water (15 mL) and separated. Thenthe aqueous layer was extracted with EtOAc (3×20 mL). The combinedorganic layers were washed with brine (20 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by reverse phase flash column to give tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(340 mg, 481 umol, 55.5% yield, 98.7% purity) as brown oil. ES+APCI MSm/z 698.4 [M+H]⁺.

Step H:[4-[4-[3-(cyanomethyl)piperazin-1-yl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate:To a solution of tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(140 mg, 201 umol) in DCM (0.2 mL) was added TFA (229 mg, 2.01 mmol, 148uL) at 15° C. and the mixture was stirred at 15° C. for 5 hours. Thereaction mixture was concentrated under vacuum to give[4-[4-[3-(cyanomethyl)piperazin-1-yl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (170 mg, crude, 2 TFA) as brown oil.

Step I:[4-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate:To a solution of[4-[4-[3-(cyanomethyl)piperazin-1-yl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (170 mg, 206 umol, 2 TFA) and DIEA (213 mg, 1.65mmol, 287 uL) in DCM (0.3 mL) was added prop-2-enoyl prop-2-enoate (38.9mg, 309 umol) at 0° C. and this mixture was stirred at 15° C. for 1hour. The reaction mixture was quenched by water (0.5 mL), thenconcentrated under vacuum. The residue (DCM:MeOH=10:1) was purified bysilica gel chromatography (from PE:EtOAc=2:1 to EtOAc:MeOH=0:1) to give[4-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate(170 mg, 182 umol, 88.7% yield, 70.0% purity) as brown oil ES+APCI MSm/z 652.6 [M+H]⁺.

Step J:2-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile:To a solution of[4-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate(170 mg, 261 umol) in THF (1.5 mL) was added NaOH (2 M, 1.5 mL) and thereaction was stirred at 15° C. for 6 hours. The reaction mixture wasneutralized by HCOOH (20%, 0.1 mL) to PH=7. The resulting mixture wasextracted with DCM (3×5 mL), the combined organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure togive a residue. The residue was purified by prep-HPLC (column: Luna C18150*25 5 u; mobile phase: [water (0.225% Formic Acid)-ACN]; B %:12%-39%, 10 min) to give2-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(6.88 mg, 11.6 umol, 4.44% yield, 95.6% purity) as yellow solid. ES+APCIMS m/z 568.5[M+H]⁺.

Example 1792-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: [(3R)-1-methylpyrrolidin-3-yl]methanol: To the solution oftert-butyl (3R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (1 g, 4.97mmol) in THF (40 mL) was added LiAlH₄ (377 mg, 9.94 mmol) at 0° C., thenthe mixture was warmed to 70° C. and stirred at 70° C. for 4 hours. Thereaction mixture was quenched by saturated Na₂SO₄ (3 mL) and filtered,the filter cake was washed with THF (5×20 mL). The combined organicphase was concentrated under vacuum to give[(3R)-1-methylpyrrolidin-3-yl]methanol (820 mg, crude) as yellow oil. ¹HNMR (400 MHz, chloroform-d) δ=3.66-3.62 (dd, J=4.8, 10.0 Hz, 1H),3.53-3.49 (dd, J=5.6, 10.0 Hz, 1H), 3.35-3.18 (m, 1H), 2.77-2.68 (m,1H), 2.59-2.53 (m, 1H), 2.52-2.45 (m, 1H), 2.40-2.33 (m, 1H), 2.32 (s,3H), 2.31-2.26 (m, 1H), 2.04-1.93 (m, 1H), 1.69-1.59 (m, 1H)

Step B: tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To the solution of tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 773 umol) and [(3R)-1-methylpyrrolidin-3-yl]methanol (178 mg,1.55 mmol) in toluene (10 mL) was added t-BuONa (111 mg, 1.16 mmol) andthis mixture stirred at 15° C. for 0.5 hour. To the mixture was addedethyl acetate (20 mL) and water (15 mL), then extracted with ethylacetate (3×20 mL). The combined organic layers were washed with brine(20 mL). The combined organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by reversed phase flash column (ACN/Water (0.1% FormicAcid)=42%) to give tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(180 mg, 245 umol, 31.7% yield, 95.0% purity) as brown solid. ES+APCI MSm/z 698.6 [M+H]⁺.

Step C:[4-[4-[3-(cyanomethyl)piperazin-1-yl]-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate: A mixture of tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(180 mg, 258 umol) and TFA (588 mg, 5.16 mmol, 382 uL) was stirred at20° C. for 1.5 hours. The reaction mixture was concentrated under vacuumto give[4-[4-[3-(cyanomethyl)piperazin-1-yl]-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (200 mg, crude, 2 TFA) as a brown oil.

Step D:[4-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate: To the solution of[4-[4-[3-(cyanomethyl)piperazin-1-yl]-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (200 mg, 242 umol, 2 TFA) and DIEA (470 mg, 3.63mmol, 633 uL) in DCM (0.6 mL) was added prop-2-enoyl prop-2-enoate (30.5mg, 242 umol) at 0° C. and the reaction stirred at 15° C. for 1 hour.The reaction mixture was concentrated under vacuum. The residue waspurified by silica gel chromatography (PE:EA=2:1˜0:1 toDCM:MeOH=50:1˜1:1) to give[4-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (630 mg, crude) as brown oil. ES+APCI MS m/z652.6 [M+H]⁺.

Step E:2-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile:To a solution of[4-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (630 mg, 966 umol) in THF (3 mL) was added NaOH(2 M, 3 mL) at 18° C. and the mixture stirred at 18° C. for 2 hours. Thereaction mixture was neutralized by HCOOH (20%, 0.5 mL) to PH=7. Theresulting mixture was extracted with DCM (3×5 mL), the combined organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by prep-HPLC (column:Phenomenex Gemini 150*25 mm*10 um; mobile phase: [water (10 mMNH4HCO3)-ACN]; B %: 35%-65%, 3 min) to give2-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(9.4 mg, 15.8 umol, 1.64% yield, 95.5% purity) as yellow solid. ES+APCIMS m/z 568.5[M+H]⁺.

Example 1804-(3-(4-(piperazin-1-yl)-7-(5-(trifluoromethyl)-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yloxy)propyl)morpholine

Step A:2-[[4-bromo-5-(trifluoromethyl)indazol-1-yl]methoxy]ethyl-trimethyl-silane:To a solution of 4-bromo-5-(trifluoromethyl)-1H-indazole (650 mg, 2.45mmol, 1 eq) in DMF (30 mL) was added NaH (117.71 mg, 2.94 mmol, 60%purity, 1.2 eq) at 0° C. After being stirred at 0° C. for 1 hour, asolution of 2-(chloromethoxy)ethyltrimethyl-silane (531.56 mg, 3.19mmol, 564.29 uL, 1.3 eq) in DMF (10 mL) was added dropwise. The mixturewas warmed to 15° C. and stirred for 2 hours. The mixture was quenchedwith saturated aqueous ammonium chloride solution (50.0 mL), dilutedwith water (100.0 mL) and then extracted with ethyl acetate (3×100.0mL). The organic layer was dried over Na₂SO₄, filtered and concentratedunder vacuum to give a residue. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=10:1),2-[[4-bromo-5-(trifluoromethyl)indazol-1-yl]methoxy]ethyl-trimethyl-silane(680 mg, 1.70 mmol, 69.44% yield, 99.0% purity) was obtained as acolorless oil. ES+APCI MS m/z 395.0[M+H]⁺.

Step B. tert-butyl4-[2-(3-morpholinopropoxy)-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:A mixture of2-[[4-bromo-5-(trifluoromethyl)indazol-1-yl]methoxy]ethyl-trimethyl-silane(444.35 mg, 1.12 mmol, 1.3 eq), tert-butyl4-[2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(400 mg, 864.71 umol, 1 eq), RuPhos (80.70 mg, 172.94 umol, 0.2 eq),Pd₂(dba); (118.77 mg, 129.71 umol, 0.15 eq), and Cs₂CO₃ (845.21 mg, 2.59mmol, 3 eq) in toluene (40 mL) was degassed and purged with N₂ 3 times,and the mixture was stirred at 90° C. for 12 hrs under nitrogen. Thereaction mixture was concentrated under reduced pressure to removetoluene. The residue was diluted with water 100 mL and extracted withEthyl acetate 300 mL (100 mL×3). The combined organic layers were washedwith water 300 mL (100 mL×3), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by column chromatography (SiO2, DCM:CH₃OH=30:1 to 20:1).tert-butyl4-[2-(3-morpholinopropoxy)-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(400 mg, 446.87 umol, 51.68% yield, 86.8% purity) was obtained as ayellow solid. ES+APCI MS m/z 773.3 [M+H]⁺.

Step C:4-[3-[[4-piperazin-1-yl-7-[5-(trifluoromethyl)-1H-indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propyl]morpholine:To a solution oftert-butyl-4-[2-(3-morpholinopropoxy)-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5Hpyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(100 mg, 111.72 umol, 1 eq) in DCM (2 mL) was added TFA (254.77 mg, 2.23mmol, 165.43 uL, 20 eq) at 25° C. The reaction mixture was stirred at25° C. for 12 hours. The reaction mixture was concentrated in vacuum.4-[3-[[4-piperazin-1-yl-7-[5-(trifluoromethyl)-1H-indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propyl]morpholine(200 mg, crude, TFA) was obtained as a brown color oil. The crudeproduct was used directly to the next step without further purification.ES+APCI MS m/z 547.5[M+H]⁺.

Step D.1-[4-[2-(3-morpholinopropoxy)-7-[5-(trifluoromethyl)-1H-indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a solution of4-[3-[[4-piperazin-1-yl-7-[5-(trifluoromethyl)-1H-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propyl]morpholine(200 mg, TFA) and DIEA (600 mg, 4.64 mmol, 808.63 uL) in DCM (2 mL) wasadded dropwise prop-2-enoyl prop-2-enoate (13 mg, 103.08 umol) at −50°C. The mixture was stirred at −50° C. for 30 min. The mixture wasquenched with water and extracted with ethyl acetate (50 mL), theorganic layer was washed with water (1×20 mL) and brine (1×20 mL). Theseparated organic layer was dried over sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by prep-HPLC (FAcondition) column: Luna C18 150*25 5 u; mobile phase: [water (0.225%FA)-ACN]; B %: 15%-36%, 10 min].1-[4-[2-(3-morpholinopropoxy)-7-[5-(trifluoromethyl)-1H-indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(18.26 mg, 28.12 mmol, two steps 23%, 99.6% purity, FA) was obtained asa yellow solid. ES+APCI MS m/z 601.4 [M+H]⁺.

Example 1811-(4-(2-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(5-methyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A. benzyl4-(2-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:To a solution of 3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propan-1-ol (107 mg, 681 umol) in THF (2 mL) was addedt-BuONa (98.1 mg, 1.02 mmol) followed by benzyl4-[2-methylsulfinyl-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(230 mg, 340 umol). The mixture was stirred at 0° C. for 1 hour. Themixture was poured into water (10 mL) and extracted with DCM (2×10 mL).The organic layer was dried over Na₂SO₄, filtered and concentrated. Theobtained product was purified by prep-HPLC (column: Phenomenex SynergiC18 150*25*10 um, mobile phase: [water (0.1% TFA)-ACN]; B %: 25%-55%, 12min) to give benzyl4-(2-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(110 mg, 143 umol, 42.0% yield) was obtained as yellow solid. ¹H NMR(400 MHz, Chloroform-d) δ 8.08-8.01 (m, 1H), 7.45-7.43 (m, 4H),7.37-7.31 (m, 3H), 5.76 (s, 2H), 5.24 (s, 2H), 4.76-4.63 (m, 1H),4.60-4.45 (m, 3H), 4.42 (s, 2H), 4.36-4.24 (m, 1H), 3.96-3.83 (m, 2H),3.79-3.65 (m, 8H), 3.64-3.53 (m, 6H), 3.12-2.92 (m, 1H), 2.90-2.77 (m,2H), 2.48 (s, 3H), 2.44-2.41 (m, 1H), 2.36-2.12 (m, 3H), 0.98-0.93 (m,2H), 0.01-0.03 (m, 9H)

Step B. tert-butyl4-(2-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:To a solution of benzyl 4-(2-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(90 mg, 117 umol) and BOC₂O (51.1 mg, 234.1 umol, 53.8 uL) in MeOH (2mL) was added Pd/C (10%, 50 mg) under an Ni atmosphere. The suspensionwas degassed under vacuum and purged with H₂ several times. The mixturewas stirred under H₂ (15 psi) at 40° C. for 12 hours. The mixture wasfiltered and concentrated. The residue was purified by prep-TLC (SiO₂,DCM/MeOH=10:1) to give tert-butyl4-(2-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(30 mg, 40.8 umol). ES+APCI MS m/z 735.6 [M+H]⁺.

Step C:(1S,4S)-5-(3-((7-(5-methyl-1H-indazol-4-yl)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)propyl)-2-oxa-5-azabicyclo[2.2.1]heptane:To a solution of tert-butyl 4-(2-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(30 mg, 40.8 umol) in DCM (0.5 mL) was added TFA (770 g, 6.75 mmol)dropwise. The mixture was stirred at 15° C. for 2 hours. The mixture wasconcentrated under vacuum to give(1S,4S)-5-(3-((7-(5-methyl-1H-indazol-4-yl)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)propyl)-2-oxa-5-azabicyclo[2.2.1]heptane(30 mg, crude). ES+APCI MS m/z 505.5[M+H]⁺.

Step D.1-(4-(2-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(5-methyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one:To a solution of(1S,4S)-5-(3-((7-(5-methyl-1H-indazol-4-yl)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)propyl)-2-oxa-5-azabicyclo[2.2.1]heptane(20 mg, 39.6 umol, 1 eq) and DIEA (30.7 mg, 238 umol, 41.4 uL, 6 eq) inDCM (2 mL) was added prop-2-enoyl prop-2-enoate (4.00 mg, 31.7 umol, 0.8eq) at −50° C. The mixture was stirred at −40-−20° C. for 0.5 hour. Themixture was concentrated under vacuum. The obtained product was purifiedby prep-HPLC (column: Phenomenex Gemini 150*25 mm*10 um; mobile phase:[water (0.05% ammonia hydroxide v/v)-ACN]; B %: 35%-65%, 12 min). Theproduct1-(4-(2-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(5-methyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one(6.48 mg, 11.2 umol, two steps 28.3% yield, 96.8% purity) was obtainedas white solid. ES+APCI MS m/z 559.5[M+H]⁺.

Example 1822-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a mixture of tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(190 mg, 403 umol), (4-bromo-2-naphthyl) 2,2-dimethylpropanoate (248 mg,806 umol) and Cs₂CO₃ (394 mg, 1.21 mmol) in toluene (5 mL) was addedXPHOS Palladacycle Gen 3 (34.1 mg, 40.29 umol) and the reaction mixturestirred at 70° C. for 4 hours under N₂. Upon completion, the reactionmixture was purified by silica gel chromatography (PE:EA3:1 to 0:1) togive tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(95 mg, 118 umol). ES+APCI MS m/z 698.4 [M+H]⁺.

Step B:[4-[4-[3-(cyanomethyl)piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate. To a solution of tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(40 mg, 57.3 umol) in DCM (0.1 mL) was added TFA (154 mg, 1.35 mmol) at15° C. The reaction mixture was stirred at 15° C. for 1 hour. Uponcompletion, the solvent was removed under vacuum to give[4-[4-[3-(cyanomethyl)piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate(47 mg, 56.9 umol).

Step C:[4-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate. To a solution of[4-[4-[3-(cyanomethyl)piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (47 mg, 56.9 umol) and DIEA (58.9 mg, 455 umol)in DCM (1 mL) was added prop-2-enoyl prop-2-enoate (10.8 mg, 85.4 umol)at 0° C. The reaction mixture was stirred at 15° C. for 1 hour. Uponcompletion, the reaction mixture was quenched by addition of a drop ofwater. The residue was purified by silica gel chromatography(PE:EtOAc=3:1 to EtOAc:MeOH=3:1) to give[4-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (130 mg, crude). ES+APCI MS m/z 652.5 [M+H]⁺.

Step D:2-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of[4-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (250 mg, 384 umol) in THF (1.5 mL) was added NaOH(2 M, 1.5 mL) in water. The reaction mixture was stirred at 15° C. for 9hours. Upon completion, the reaction mixture was acidified by additionof two drops of formic acid (20% in water) to reach a pH=7 and theaqueous layer extracted with DCM (5×10 mL). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated under vacuum. Theresidue was purified by prep-HPLC (column: Boston Green ODS 150*30 5 u;mobile phase: [water (0.225% FA)-ACN]; B %: 20%-47%, 10 min) to give2-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(13.1 mg, 21.2 umol). ES+APCI MS m/z 568.5 [M+H]⁺.

Example 1832-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: tert-butyl2-(cyanomethyl)-4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of tert-butyl2-(cyanomethyl)-4-[2-methylsulfinyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(300 mg, 549 umol) and [(2S)-1-methylpyrrolidin-2-yl]methanol (126 mg,1.10 mmol, 130 uL) in toluene (6.00 mL) was added t-BuONa (105 mg. 1.10mmol). The mixture was stirred at 20° C. for 0.25 hour. Upon completion,the mixture was filtered and the filtrate was concentrated. The residuewas purified by silica gel chromatography (EA/MeOH 50/1 to 10/1) to givetert-butyl2-(cyanomethyl)-4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(300 mg, 427 umol). ES+APCI MS m/z 598.6 [M+H]⁺.

Step B:2-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl2-(cyanomethyl)-4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(270 mg, 452 umol) in DCM (330 uL) was added TFA (515 mg, 4.52 mmol).The mixture was stirred at 20° C. for 0.5 hour and concentrated undervacuum. Then TFA (334 uL) was added. The mixture was stirred at 20° C.for 1 hour. Upon completion, the mixture was concentrated under vacuumto give2-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(400 mg, crude). ES+APCI MS m/z 498.4 [M+H]⁺.

Step C:2-[4-[2-[[(2R)-1-methylpyrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(276 mg, 451 umol) and DIEA (1.46 g, 11.3 mmol) in DCM (4.00 mL) wasadded prop-2-enoyl prop-2-enoate (51.2 mg, 406 umol) dropwise at 0° C.The mixture was stirred at 20° C. for 1 hour. Upon completion, themixture was diluted with water (0.5 mL) and extracted with EtOAc (2×10mL). The combined organic layers were dried over Na₂SO₄ and concentratedunder vacuum. The residue was purified by prep-HPLC (column: PhenomenexGemini 150*25 mm*10 um; mobile phase: [water (0.05% ammonia hydroxidev/v)-ACN]; B %: 55%-85%, 12 min) to give2-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(37.1 mg, 66.3 umol). ES+APCI MS m/z 552.4 [M+H]⁺.

Example 1841-[4-[7-(3-hydroxy-1-naphthyl)-2-(3-hydroxypropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

1-[4-[7-(3-hydroxy-1-naphthyl]-2-(3-hydroxypropoxy-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl]prop-2-en-1-onewas prepared following Example 136 substituting3-[tert-butyl(dimethyl)silyl]oxopropan-1-ol for2-(3-methoxypyrrolidin-1-yl)ethanol in Step B. ES+APCI MS m/z 490.3[M+H]⁺.

Example 1851-(4-(2-(3-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: 3-(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propan-1-ol: To avial was added (1R,4R)-2-Oxa-5-azabicyclo[2.2.1]heptane HCl salt (0.250g, 2.522 mmol), CH₃CN (5.04 mL) and 3-Bromo-1-propanol (0.274 mL, 3.026mmol). Then K₂CO₃ (1.05 g, 7.57 mmol) was added and the mixture waswarmed to 50° C. where it stirred for 16 hours. The mixture was thencooled to ambient temperature, diluted with CH₂Cl₂ and filtered and thesolid was washed with CH₂Cl₂. The filtrate was then concentrated and thecrude oil was purified via column chromatography (5% MeOH/DCM with 0.2%NH₄OH) to afford the product as a colorless oil.

Step B:1-(4-(2-(3-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(3-hydroxynaphthalen-1-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-ol:Synthesized according to the method of Example 127 using the followingprocedure in place of that outlined in Step D. To a vial was added3-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propan-1-ol (0.171 g,1.09 mmol) and benzyl4-(2-chloro-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.125 g, 0.218 mmol) followed by dioxane (0.435 mL). Then Cs₂CO₃ (0.213g, 0.653 mmol) was added and the mixture was heated to 100° C. for 15hours. The reaction was diluted with CH₂Cl₂, filtered and the residualsolid was washed with CH₂Cl₂. The filtrate was then dried over Na₂SO₄,filtered and concentrated. The crude residue was purified by columnchromatography (4% MeOH/DCM with 0.2% NH4OH) to afford the product as ayellow foam. ES+APCI MS m/z 571.2 [M+H]⁺.

Example 186 Benzyl4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(3-(morpholinomethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

Benzyl4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(3-morpholinomethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:Synthesized according to the method of Example 127 using the followingprocedure in place of that outlined in Step D. To a solution of benzyl4-(2-chloro-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.150 g, 0.261 mmol) and 3-(4-Morpholinomethyl)-phenylboronic acidpinacol ester hydrochloride (0.266 g, 0.784 mmol) in dioxane (2.61 mL)was added Na₂CO₃ (0.523 mL, 1.0452 mmol, 2.0M Aq). The mixture wasdegassed by argon bubbling for 5 min. ThenTetrakis(triphenylphosphine)palladium (0) (0.030 g, 0.026 mmol) wasadded and the mixture was heated to 95° C. where it stirred for 7 hours.The reaction was cooled to ambient temperature and then diluted withCHCl₂ and filtered. The solid was washed with CH₂Cl₂. The filtrate wasthen dried over Na₂SO₄, filtered and concentrated. The crude residue waspurified by column chromatography (30-50% EtOAc/DCM) to afford theproduct as a yellow foam. ES+APCI MS m/z 591.3 [M+H]⁺.

Example 187(R)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

(R)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one.This compound was prepared following Example 127 substitutingN-Methyl-D-prolinol for N-Methyl-L-prolinol in Step D. ES+APCI MS m/z529.3 [M+H]⁺.

Example 188(S)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpyrrolidin-3-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

(S)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(1-methylpyrrolidin-3-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one.This compound was prepared following Example 127 substituting(3S)-(1-Methyl-pyrrolidin-3-yl)-methanol for N-Methyl-L-prolinol in StepD. ES+APCI MS m/z 529.2 [M+H]⁺.

Example 1891-(4-(2-((1-benzylpyrrolidin-3-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

1-(4-(2-((1-benzylpyrrolidin-3-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one.This compound was prepared following Example 127 substituting(1-Benzylpyrrolidin-3-yl)methanol for N-Methyl-L-prolinol in Step D.ES+APCI MS m/z 605.3 [M+H]⁺.

Example 1901-(4-(2-((1-cyclopropylpyrrolidin-3-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

1-(4-(2-((1-cyclopropylpyrrolidin-3-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one.This compound was prepared following Example 127 substituting(1-Cyclopropyl-3-pyrrolidinyl)methanol for N-Methyl-L-prolinol in StepD. ES+APCI MS m/z 555.3 [M+H]⁺.

Example 1911-((2S,6R)-4-(7-(3-hydroxynaphthalen-1-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2,6-dimethylpiperazin-1-yl)prop-2-en-1-one

Step A: Benzyl4-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:A suspension of benzyl2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (500mg, 1.48 mmol), tert-butyl cis-2,6-dimethylpiperazine-1-carboxylate (349mg, 1.63 mmol) and DIEA (0.26 mL) in N,N-dimethylacetamide (1 mL) wasstirred at r.t. overnight. The reaction mixture was divided betweenEtOAc (15 mL) and 1 M NaHCO₃ (5 mL) and the layers separated. Theorganic layer was washed with 2M Na₂CO₃ and brine (2 mL each), driedover Na₂SO₄ and evaporated in vacuo. The residue was chromatographed onsilica gel Redisep 24 g column using 20 to 50% EtOAc in hexane as eluentto give a colorless solid (0.440 g, 58%). ES+APCI MS m/z 516.2 [M+H]⁺.

Step B: Benzyl4-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-2-(3-morpholinopropoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:A mixture of benzyl4-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(400 mg, 0.775 mmol), 3-morpholinopropan-1-ol (400 mg, 2.33 mmol, 5eq.), cesium carbonate (1.26 g, 3.88 mmol, 5 eq.) and dioxane (3 mL) ina 4-mL vial was purged with nitrogen. The vial was capped and themixture stirred at 110° C. for 20 h, then at 120° C. overnight. Thereaction was cooled, diluted with EtOAc (10 mL), filtered through Celiteand evaporated in vacuo. The product was purified by chromatography onsilica, Redisep 40 g, using 2 to 10% MeOH/DCM+0.2% NH₄OH as eluent togive a light-yellow amorphous solid (272 mg, 56%).

Step C: tert-butyl(2S,6R)-2,6-dimethyl-4-(2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:A mixture of benzyl4-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-2-(3-morpholinopropoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(272 mg, 0.095 mmol), palladium on carbon (50 mg, Degussa Type, 10 wt %,50% H₂O), EtOH (5 mL) and THE (5 mL) was purged with hydrogen andstirred under H₂ atmosphere (rubber balloon) for 3 hours. The reactionmixture was diluted with EtOH (3 mL), filtered through Celite and thecelite washed with EtOH (2×2 mL). The combined organics were evaporatedin vacuo and dried under high vacuum over 2 days to give an off-whitefoam (205 mg, 96%). ES-+APCI MS m/z 491.3 [M+]⁺.

Step D: tert-butyl(2S,6R)-4(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2,6-dimethylpiperazine-1-carboxylate:To a stirred suspension of tris(dibenzylideneacetone)dipalladium (0)(19mg, 0.020 mmol) in dry degassed toluene (0.5 mL) at room temperatureunder nitrogen was added(+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (24 mg, 0.038 mmol).The mixture was then heated to 100° C. for 15 minutes. The resulted darkmixture was cooled to room temperature and solid sodium-t-butoxide (39mg, 0.41 mmol) was added, followed by a solution of3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (82 mg, 0.25mmol) and tert-butyl(2S,6R)-2,6-dimethyl-4-(2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(100 mg, 0.20 mmol) in degassed dry toluene (0.5 mL). The flask wasclosed and heated with stirring to 100° C. for 30 min. The reactionmixture was cooled and divided between EtOAc (20 mL) and water (10 mL).The organic layer was separated and washed with brine, dried over Na₂SO₄and evaporated in vacuo. The product was purified by chromatography onsilica, Redisep 40 g, using 4% MeOH+0.1% NH₄OH in DCM as eluent to givea colorless solid (87 mg, 63%). ES+APCI MS m/z 684.3 [M+H]⁺.

Step E:1-((2S,6R)-4(7-(3-hydroxynaphthalen-1-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2,6-dimethylpiperazin-1-yl)prop-2-en-1-one:Tert-butyl(2S,6R)-4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2,6-dimethylpiperazine-1-carboxylate(87 mg, 0.129 mmol) was dissolved in 1M TFA/DCM. The reaction mixtureturned red-brown, then dark-red. LCMS indicated non-selectivedeprotection of Boc and MOM. After stirring 30 min at room temperature,0.2 mL of additional TFA was added and the reaction mixture was left atroom temperature for another 30 min. The resulted biphasic mixture wasvaporated in vacuo, divided between water (5 mL) and DCM (10 mL)+NEt₃(0.5 mL) and the organic layer separated. The organic layer was driedover Na₂SO₄ and evaporated in vacuo. The residue was purified bychromatography on silica, Redisep 40 g, using 6% MeOH in DCM+0.2% NH₄OHas eluent to give another residue which was repurified on reverse phase,C18, 5-95% MeCN-H₂O+0.1% TFA to give product assumed to be the bis-saltwith TFA (1.35 mg, 1.3%). ES+APCI MS m/z 587.3 [M+H]⁺.

Example 192(R)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpiperidin-3-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

(R)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpiperidin-3-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one.This compound was prepared following Example 127 substituting3-Piperidinemethanol,1-methyl-,(3R)- for N-Methyl-L-prolinol in Step).ES+APCI MS m/z 543.3 [M+H]⁺.

Example 1931-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((4-methylmorpholin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((4-methylmorpholin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one.This compound was prepared following Example 127 substituting(4-methyl-2-morpholinyl)methanol for N-Methyl-L-prolinol in Step D.ES+APCI MS m/z 545.3 [M+H]⁺.

Example 1941-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((4-methylmorpholin-3-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((4-methylmorpholin-3-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-viprop-2-en-1-one. This compound was prepared following Example 127substituting 4-Methyl-3-(hydroxymethyl)morpholine forN-Methyl-L-prolinol in Step D. ES+APCI MS m/z 545.2 [M+H]⁺.

Example 195(R)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpiperidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

(R)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpiperidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one.This compound was prepared following Example 127 substituting(R)-(1-Methylpiperidin-2-yl)methanol for N-Methyl-L-prolinol in Step D.ES+APCI MS m/z 543.3 [M+H]⁺.

Example 196(S)-1-(4(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpiperidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

(S)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpiperidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one.This compound was prepared following Example 127 substituting(S)-(1-Methylpiperidin-2-yl)methanol for N-Methyl-L-prolinol in Step D.ES+APCI MS m/z 543.2 [M+H]⁺.

Example 197(S)-1-(4-(2-((1-ethylpyrrolidin-2-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

(S)-1-(4-(2-((1-ethylpyrrolidin-2-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one.This compound was prepared following Example 127 substituting[(2S)-1-Ethyl-2-pyrrolidinyl]methanol for N-Methyl-L-prolinol in Step D.ES+APCI MS m/z 543.3 [M+H]⁺.

Example 198(S,E)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)but-2-en-1-one

S,E)-1-(4(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)but-2-en-1-one.This compound was prepared following Example 127 substitutingtrans-Crotonyl chloride for Acryloyl Chloride in Step F. ES+APCI MS m/z543.2[M+H]⁺.

Example 199(S,E)-4-(dimethylamino)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)but-2-en-1-one

(S,E)-4-(dimethylamino)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)but-2-en-1-one.This compound was prepared following Example 127 substituting thefollowing procedure for step F.7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-4a,5,6,7,8,8a-hexahydropyrido[3,4-d]pyrimidine(150 mg, 0.288 mmol) was dissolved in DCM (5 mL) and treated with(2E)-4-(Dimethylamino)but-2-enoic acid (74.4 mg, 0.576 mmol) and Hunig'sbase (252 μl, 1.44 mmol). To this mixture was added EDC (55.2 mg, 0.288mmol) and HOBT (38.9 mg, 0.288 mmol) neat as powders. The reactionmixture was stirred at room temperature for 1 hour and heated to 35° C.for an additional 3 hours. The reaction mixture was concentrated invacuo and purified on the CombiFlash (0%-15% DCM/MeOH w/1% NH4OHmodifier). All fractions containing clean desired product were combinedand concentrated in vacuo to afford(E)-4-(dimethylamino)-1-(4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4a,5,6,7,8,8a-hexahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)but-2-en-1-one(105 mg, 0.166 mmol, 57.7% yield). The product followed the rest ofExample 127 accordingly to give(S,E)-4-(dimethylamino)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)but-2-en-1-one(14.8 mg, 0.025 mmol, 15.2% yield). ES+APCI MS m/z 586.3 [M+H]⁺.

Example 200(S)-1-(4-(2-((1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

(S)-1-(4-(2-((1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one.This compound was prepared following Example 127 substitutingnaphthalen-1-yl trifluoromethanesulfonate for3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate in Step Cand not performing step F. ES+APCI MS m/z 513.3 [M+H]⁺.

Example 2011-((R)-2-methyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

1-(((R)-2-methyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one.This compound was prepared following Example 127 substituting (R)-benzyl2-methylpiperazine-1-carboxylate for benzyl piperazine-1-carboxylate inStep A and substituting naphthalen-1-yl trifluoromethanesulfonate for3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate in Step Cand not performing step F. ES+APCI MS m/z 527.3 [M+H]⁺.

Example 2021-((S)-4-(7-(3-hydroxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one

1-((S)-4-(7-(3-hydroxynaphthalen-1-yl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one.This compound was prepared following Example 127 substituting benzyl(S)-3-methylpiperazine-1-carboxylate for benzyl piperazine-1-carboxylatein Step A. ES+APCI MS m/z 543.3 [M+H]⁺.

Example 2031-((S)-4-(7-(3-hydroxynaphthalen-1-yl)-2-(((R)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one

1-((S)-4-(7-(3-hydroxynaphthalen-1-yl)-2-(((R)-1-methylpyrrolidin-2-yl)methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one.This compound was prepared following Example 127 substituting benzyl(S)-3-methylpiperazine-1-carboxylate for benzyl piperazine-1-carboxylatein Step A and substituting N-Methyl-D-prolinol for N-Methyl-L-prolinolin Step D. ES+APCI MS m/z 543.3 [M+H]⁺.

Example 2041-(4-(2-((1-cyclopropylpiperidin-4-yl)amino)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: Benzyl4-(2-((1-cyclopropylpiperidin-4-yl)amino)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:A mixture of benzyl4-(2-chloro-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(75 mg, 0.13 mmol), 1-cyclopropylpiperidin-4-amine (55 mg, 0.39 mmol)and dioxane (0.5 mL) was heated to 120° C. for 36 h. The reactionmixture was cooled to room temperature, divided between EtOAC (10 mL)and water (3 mL) and the layers separated. The organic layer was washedwith brine, dried over Na₂SO₄ and evaporated in vacuo and the residuechromatographed on silica, Redisep 24 g, using 6 to 10% MeOH in DCM+0.2%NH₄OH as eluent to give a colorless solid (43 mg, 49%). ES+APCI MS m/z678.3 [M+H]⁺.

Step B:1-(4-(2-((1-cyclopropylpiperidin-4-yl)amino-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one:A mixture of benzyl4-(2-((1-cyclopropylpiperidin-4-yl)amino)-7-(3-(methoxymethoxy)-naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(43 mg, 0.063 mmol), palladium on carbon (20 mg, Degussa Type, 10 wt %,50% H₂O), EtOH (1.5 mL) and THF (1.5 mL) was purged with hydrogen andstirred under H₂ atmosphere (rubber balloon) for 3 hours. The mixturewas diluted with EtOH (3 mL), filtered through Celite and the celitewashed with EtOH (2×2 mL). The combined organics were evaporated invacuo. The residue was dissolved in DCM (5 mL) and cooled on ice-saltbath with stirring. Triethylamine (0.03 mL) was next added at once,followed by acryloyl chloride (10 μL). After 1 min at −5° C. thereaction was quenched with NH₄OH (0.05 mL) and evaporated in vacuo. Theresidue was stirred 5 min with DCM (5 mL), filtered and chromatographedon silica gel, Redisep 12 g, using 6 to 20% MeOH in DCM+0.2% NH₄OH aseluent to give a colorless solid (22 mg, 48%). ES+APCI MS m/z 598.3[M+H]⁺.

Step C:1-(4-(2-((1-cyclopropylpiperidin-4-yl)amino)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one:To a stirred solution of1-(4-(2-((1-cyclopropylpiperidin-4-yl)amino)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one(22 mg, 0.037 mmol) in a mixture of MeOH and THF 1:1 (3 mL) was added 6Maqueous HCl (0.3 mL, 34 eq.) all at once and the resulting solution washeated with stirring at 50° C. for 1.5 hours. The reaction mixture wascooled to room temperature, divided between EtOAc (15 mL) and 0.5MNa₂CO₃ (10 mL) and the organic layer separated. The combined organicswere washed with brine (3 mL), dried over Na₂SO₄ and evaporated invacuo. The residue was chromatographed on silica, Redisep 12 g, using 8to 10% MeOH in DCM+0.2% NH₄OH as eluent to give a colorless solid (15mg, 74%). ES+APCI MS m/z 554.3 [M+H]⁺.

Example 2051-(4-(7-(6-hydroxyquinolin-8-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: Benzyl4-(7-(6-(methoxymethoxy)quinolin-8-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:To a stirred suspension of tris(dibenzylideneacetone)dipalladium (0) (17mg, 0.019 mmol) in degassed dry toluene (0.5 mL) under nitrogen at roomtemperature was added (+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl(24 mg, 0.038 mmol) and the mixture was heated to 100° C. for 15minutes. The dark mixture was cooled to room temperature and solidsodium-t-butoxide (36 mg, 0.38 mmol) was then added, followed by asolution of 8-bromo-6-(methoxymethoxy)quinoline (61 mg, 0.23 mmol) andbenzyl4-(2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(94 mg, 0.19 mmol) in degassed dry toluene (0.5 mL). The flask wasclosed and heated to 100° C. for 1 hour. The reaction mixture was cooledto room temperature, divided between EtOAc (15 mL) and water (5 mL) andthe organic layers separated. The organic layer was washed with brine,dried over Na₂SO₄ and evaporated in vacuo. The residue waschromatographed on silica gel. Redisep 24 g, using 4 to 10% MeOH indichloromethane (+0.2% NH₄OH) as eluent to give a yellow solid (28 mg,22%). ES+APCI MS m/z 684.3 [M+H]⁺.

Step B:1-(4-(7-(6-(methoxymethoxy)quinolin-8-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one:A mixture of benzyl4-(7-(6-(methoxymethoxy)quinolin-8-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(28 mg, 0.095 mmol), Pd/C (15 mg, Degussa Type, 10 wt %, 50% H₂O), EtOH(2 mL) and THF (2 mL) was purged with hydrogen and stirred under H₂atmosphere (rubber balloon) for 2 hours. The reaction mixture wasdiluted with EtOH (3 mL), filtered through Celite and the celite washedwith EtOH (2×2 mL) and the combined organics evaporated in vacuo. Theresulted solid was dissolved in DCM (5 mL) and cooled in an ice-saltbath with stirring. Triethylamine (0.04 mL, 3 eq.) was then added atonce followed by acryloyl chloride (16 μL, 2 eq.). After 1 min at −5° C.the reaction was quenched with NH₄OH (0.05 mL) and evaporated in vacuo.The mixture was filtered through a cotton plug, chromatographed onsilica gel, Redisep 12 g, using 6 to 10% MeOH in DCM+0.2% NH₄OH aseluent to give another residue which was repurified on reverse phase,C18, 5 to 95% MeCN, +0.1% HCO₂H to give product which was assumed to bethe bis-formate salt as a yellow solid (12 mg, 42%). ES+APCI MS m/z604.2 [M+H]⁺.

Step C:1-(4-(7-(6-hydroxyquinolin-8-yl)-2-(3-morpholinopropoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one:To a stirred solution of1-(4-(7-(6-(methoxymethoxy)quinolin-8-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one(12 mg, 0.017 mmol) in a mixture of MeOH and THF 1:1 (1 mL) was added 6Maqueous HCl (0.1 mL, 35 eq.) at once and the solution was heated withstirring at 50° C. for 1.5 h. The reaction mixture was cooled to roomtemperature, divided between EtOAc (15 mL) and 0.5M Na-phosphate bufferwith pH 8 (5 mL) and the layers separated. The combined organics werewashed with brine (1 mL), dried over Na₂SO₄ and evaporated in vacuo. Theproduct was purified by chromatography on silica, Redisep 12 g, using 7to 10% MeOH in DCM+0.2% NH₄OH as eluent to give a residue which wasrepurified by reverse phase chromatography, C18, 5 to 95% MeOH+0.1%TFA,) to give product as the tris TFA salt as a colorless solid (4.87mg, 31%). ES+APCI MS m/z 560.3 [M+H]⁺.

Example 2061-(4-(2-(3-(3-azabicyclo[3.1.0]hexan-3-yl)propoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: 3-(3-azabicyclo[3.1.0]hexan-3-ylpropan-1-ol. A mixture of3-azabicyclo[3.1.0]hexane hydrochloride (200 mg, 1.67 mmol),3-bromopropan-1-ol (166 μL, 1.84 mmol, 1.1 eq.), K₂CO₃ (0.69 g, 5.02mmol, 3 eq.), NaI (251 mg, 1.67 mmol, 1 eq.) and acetonitrile (2 mL) ina 4-mL vial was flushed with N₂. The vial was capped and stirred at roomtemperature for 2 days. The mixture was diluted with water (2 mL) andextracted with ether (15 mL). The ether solution was washed with brine,dried over Na₂SO₄ and decanted into a pear-shaped flask andtrifluoroacetic acid (128 μL, 1 eq) added and the mixture wasconcentrated to ˜5 mL. The upper etherial layer was decanted anddiscarded, the residual oily liquid was dried under vacuum overnight.The oily liquid was diluted with water (0.5 mL) then ether (10 mL) wasadded with stirring followed by 50% NaOH (0.2 mL, 2.5 mmol, 2 eq.). Thelayers were separated, the organic solution was dried over KOH andcarefully concentrated under nitrogen to yield crude3-(3-azabicyclo[3.1.0]hexan-3-yl)propan-1-ol as colorless oil. Used onthe next stage without further purification.

Step B: Benzyl4-(2-(3-(3-azabicyclo[3.1.0]hexan-3-yl)propoxy)-7(3-(methoxymethoxy)-naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:A mixture of benzyl4-(2-chloro-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(75 mg, 0.13 mmol), crude 3-(3-azabicyclo[3.1.0]hexan-3-yl)propan-1-ol(55 mg, 0.39 mmol, 3 eq.), Cs₂CO₃ (213 mg, 0.65 mmol, 5 eq.) and dioxane(0.5 mL) in a 1.7-mL vial was purged with nitrogen. The vial was cappedand stirred at 120° C. over the weekend. The reaction mixture wascooled, divided between EtOAc (15 mL) and water (5 mL) and the layersseparated. The organic layer was washed with brine, dried over Na₂SO₄,evaporated in vacuo and the residue chromatographed on silica gel,Redisep 24 g, using 4 to 10% MeOH+1% NH₄OH as eluent to give product.ES+APCI MS m/z 679.3 [M+H]⁺.

Step C:1-(4-(2-(3-(3-azabicyclo[3.1.0]hexan-3-yl)propoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one:A mixture of benzyl4-(2-(3-(3-azabicyclo[3.1.0]hexan-3-yl)propoxy)-7-(3-(methoxymethoxy)-naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(49 mg, 0.072 mmol), palladium on carbon (12 mg, Degussa Type, 10 wt %,50% H₂O), EtOH (1.5 mL) and THF (1.5 mL) was purged with hydrogen andstirred under H₂ atmosphere (rubber balloon) for 3 hours. The reactionmixture was diluted with EtOH (3 mL), filtered through Celite and thecelite washed with EtOH (2×2 mL). The combined organics were evaporatedin vacuo. The resulted colorless solid was dissolved in DCM (5 mL),cooled in an ice-salt bath with stirring and triethylamine (0.04 mL, 3eq.) was added at once followed by addition of acryloyl chloride (16 μL,2 eq.). After 1 min at −5° C. the reaction was quenched with NH₄OH (0.05mL) and evaporated in vacuo. The crude product was dissolved in DCM (5mL), filtered through a cotton plug and chromatographed on silica gel,Redisep 12 g, using 6 to 10% MeOH in DCM+0.2% NH₄OH as eluent to give acolorless solid (30 mg, 69%). ES+APCI MS m/z 599.3 [M+H]⁺.

Step D:1-(4-(2-(3-(3-azabicyclo[3.1.0]hexan-3-yl)propoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one:To a stirred solution of1-(4-(2-(3-(3-azabicyclo[3.1.0]hexan-3-yl)propoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one(30 mg, 0.050 mmol) in a mixture of MeOH and THF 1:1 (3 mL) was added 6Maqueous HCl (0.3 mL, 36 eq.) and the solution was heated with stirringat 50° C. for 1.5 h. The reaction mixture was cooled to roomtemperature, divided between EtOAc (20 mL) and 0.5M Na₂CO₃ (5 mL) andthe layers separated. The organic layer was washed with brine (1 mL),dried over Na₂SO₄ and evaporated in vacuo. The residue waschromatographed on silica, Redisep 12 g, using 6% MeOH in DCM+0.2% NH₄OHas eluent to give a colorless solid (20.62 mg, 74%). ES+APCI MS m/z555.4 [M+H]⁺.

Example 207(R)-1-(4-(2-(2-(3-fluoropiperidin-1-yl)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: (R)-2-(3-fluoropiperidin-1-ylethan-1-ol. A mixture ofR-3-fluoropiperidine hydrochloride (209 mg, 1.50 mmol),2-bromoethan-1-ol (117 μL, 1.65 mmol, 1.1 eq.), K₂CO₃ (0.62 g, 4.5 mmol,3 eq.), sodium iodide (225 mg, 1.5 mmol, 1 eq.) and acetonitrile (2 mL)in a 4-mL vial was flushed with N₂. The vial was capped and stirred atroom temperature for 2 days. The resulted suspension was diluted withwater (2 mL) and extracted with ether (15 mL). The ether solution waswashed with brine, dried over Na₂SO₄ and decanted into a pear-shapedflask and trifluoroacetic acid (115 μL, 1 eq) was added and the mixturewas concentrated to ˜5 mL. The upper ethereal layer was decanted, theresidual oily liquid was dried under vacuum overnight. The oily liquidwas diluted with water (0.5 mL) and ether (10 mL) with stirring,followed by addition of 50% NaOH (0.2 mL, 2.5 mmol, 2 eq.). The layerswere separated, the organic solution was dried over KOH, filtered andcarefully concentrated under nitrogen to yield crude amino alcohol as acolorless oil (120 mg, 54%).

Step B: Benzyl(R)-4-(2-(2-(3-fluoropiperidin-1-yl)ethoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:A mixture of benzyl4-(2-chloro-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(75 mg, 0.13 mmol), crude (R)-2-(3-fluoropiperidin-1-yl)ethan-1-ol (58mg, 0.39 mmol), Cs₂CO₃ (213 mg, 0.65 mmol), and dioxane (0.5 mL) in a1.7-mL vial was purged with nitrogen. The vial was capped and stirred at110° C. for 48 hours. The reaction mixture was cooled, diluted withEtOAc (1 mL), filtered through Celite and the celite washed with EtOAc(2×2 mL) and the combined organics evaporated in vacuo. The residue waschromatographed on silica, Redisep 24 g, using 6% MeOH in DCM+0.2% NH₄OHas eluent to give a colorless solid (30 mg, 34%). ES+APCI MS m/z 685.4[M+H]⁺.

Step C:(R)-1-(4(2-(2-(3-fluoropiperidin-1-yl)ethoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one:A mixture of benzyl(R)-4-(2-(2-(3-fluoropiperidin-1-yl)ethoxy)-7-(3-(methoxymethoxy)-naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(30 mg, 0.044 mmol), palladium on carbon (10 mg, Degussa Type, 10 wt %,50% H₂O), EtOH (1.5 mL) and THF (1.5 mL) was purged with hydrogen andstirred under H₂ atmosphere (rubber balloon) for 2 hours. The reactionmixture was diluted with EtOH (3 mL), filtered through Celite and thecelite washed with EtOH (2×2 mL). The combined organics were evaporatedin vacuo. The residue was dissolved in DCM (3 mL) and cooled in anice-salt bath with stirring. Triethylamine (0.02 mL, 3 eq.) was nextadded at once followed by addition of acryloyl chloride (7 μL, 2 eq.).After 1 min at −10° C. the reaction was quenched with NH₄OH (0.03 mL)and evaporated in vacuo. The residue was dissolved in DCM (5 mL),filtered, and chromatographed on silica gel, Redisep 12 g, using 6 to10% MeOH in DCM+0.2% NH₄OH in DCM as eluent to give a colorless solid(22 mg, 83%). ES+APCI MS m/z 605.3 [M+H]⁺.

Step D:(R)-1-(4-(2-(2-(3-fluoropiperidin-1-yl)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one:To a stirred solution of(R)-1-(4-(2-(2-(3-fluoropiperidin-1-yl)ethoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one(22 mg, 0.036 mmol) in a mixture of MeOH and THF 1:1 (3 mL) was added 6Maqueous HCl (0.3 mL) and the solution was heated with stirring at 50° C.for 1.5 h. The reaction mixture was cooled to room temperature, dividedbetween EtOAc (20 mL) and 0.5M Na₂CO₃ (5 mL) and the layers separated.The organic layer was washed with brine (1 mL), dried over Na₂SO₄ andevaporated in vacuo. The residue was chromatographed on silica gel,Redisep 12 g, using 6% MeOH in DCM+0.2% NH₄OH as eluent to give acolorless solid (16.86 mg, 83%). ES+APCI MS m/z 561.2 [M+H]⁺.

Example 2081-(4-(2-(3-((3R,4S)-3,4-difluoropyrrolidin-1-yl)propoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: 3-((3R,4S)-3,4-difluoropyrrolidin-1-yl)propan-1-ol. A mixture of(3R,4S)-3,4-difluoropyrrolidine hydrochloride (200 mg, 1.39 mmol),3-bromopropan-1-ol (126 μL, 1.39 mmol, 1.0 eq.), potassium carbonate(577 mg, 4.18 mmol, 3 eq.), sodium iodide (209 mg, 1.39 mmol, 1 eq.) andacetonitrile (2 mL) in a 7-mL vial was flushed with N₂. The vial wascapped and the reaction mixture was stirred at room temperature for 2days. The mixture was diluted with water (2 mL) and extracted with ether(15 mL). The ether solution was washed with brine, dried over Na₂SO₄ anddecanted into a pear-shaped flask. Trifluoroacetic acid (107 μL, 1 eq)was next added and the mixture was evaporated and dried in vacuo. Theresidue was diluted with water (0.5 mL) and washed with ether (5 mL). Tothe aqueous layer was added diethyl ether (15 mL) followed by 10M NaOH(0.2 mL, 5 mmol) and the mixture was stirred for 1 hour. The organiclayer was separated and dried over solid KOH, filtered through a cottonplug and evaporated under N₂ to give a colorless oil (80 mg, 35%) whichwas used crude in the next reaction.

Step B: Benzyl4-(2-(3-((3R,4S)-3,4-difluoropyrrolidin-1-yl)propoxy-7-(3-(methoxymethoxy)naphthalen-1-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:A mixture of benzyl4-(2-chloro-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(75 mg, 0.13 mmol), crude 2-(4,4-difluoropiperidin-1-yl)ethan-1-ol (65mg, 0.39 mmol), cesium carbonate (213 mg, 0.65 mmol, 5 eq.) and dioxane(0.5 mL) in a 1.7-mL vial was purged with nitrogen. The vial was cappedand stirred at 110° C. over the weekend. The reaction mixture was cooledto room temperature and divided between EtOAc (15 mL) and water (5 mL)and the layers separated. The organic layer was washed with brine, driedover Na₂SO₄ and evaporated in vacuo. The product was purified bychromatography on silica, Redisep 24 g, using 3% MeOH in DCM as eluentto give a colorless solid (46 mg, 50%). ES+APCI MS m/z 703.3 [M+H]⁺.

Step C:1-(4-(2-(3-((3R,4S)-3,4-difluoropyrrolidin-1-yl)propoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one:A mixture of benzyl4-(2-(3-((3R,4S)-3,4-difluoropyrrolidin-1-yl)propoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(46 mg, 0.065 mmol), palladium on carbon (15 mg, Degussa Type, 10 wt %,50% H₂O), EtOH (1 mL) and THF (1 mL) was purged with hydrogen andstirred under H₂ atmosphere (rubber balloon) for 3 hours. The reactionmixture was diluted with EtOH (3 mL), filtered through Celite and thecelite washed with EtOH (2×2 mL). The combined organics were evaporatedin vacuo. The residue was dissolved in DCM (3 mL) and cooled in anice-salt bath with stirring. Triethylamine (0.02 mL) was next addedfollowed by addition of acryloyl chloride (7 μL, 2 eq.). After 1 min at−10° C. the reaction was quenched with NH₄OH (0.03 mL) and evaporated invacuo. The residue was dissolved in DCM (3 mL), filtered and purified bychromatography on silica gel, Redisep 12 g, using 5% MeOH in DCM aseluent to give a colorless solid (29 mg, 71%). ES+APCI MS m/z 623.3[M+H]⁺.

Step D:1-(4-(2-(3-((3R,4S)-3,4-difluoropyrrolidin-1-yl)propoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one:To a stirred solution of1-(4-(2-(3-((3R,4S)-3,4-difluoropyrrolidin-1-yl)propoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one(29 mg, 0.047 mmol) in a mixture of MeOH and THF 1:1 (2 mL) was added 6Maqueous HCl (0.2 mL) and the solution was heated with stirring at 50° C.for 1.5 h. The reaction mixture was cooled to room temperature, dividedbetween EtOAc (15 mL) and 0.5M Na₂CO₃ (10 mL) and the layers separated.The organic layer was washed with brine (3 mL), dried over Na₂SO₄ andevaporated in vacuo. The residue was purified by chromatography onsilica, Redisep 12 g, using 5% MeOH in DCM as eluent to give a colorlesssolid (12.87 mg, 48%). ES+APCI MS m/z 579.2 [M+H]⁺.

Example 2091-(4-(7-(5-methyl-1H-indol-4-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: 4-bromo-5-methyl-1-(triisopropylsilyl)-1H-indole: A solution of4-bromo-5-methyl-1H-indole (100 mg, 0.476 mmol) in dry THF (2 mL) undernitrogen was cooled with stirring in an ice-salt bath. Sodium hydride(23 mg 60% in oil, 0.57 mg, 1.2 eq.) was added and the mixture wasstirred for 30 min at −5° C., then 1 h at room temperature (gasevolution ceased). Chlorotriisopropylsilane (0.10 mL, 0.48 mmol, 1 eq.)was next added and the reaction mixture was stirred at r.t. for 2 hours.The reaction was divided between EtOAc (15 mL) and water (10 mL) and thelayers separated. The organic layer was washed with water (5 mL), brine(5 mL), dried over Na₂SO₄ and evaporated in vacuo. The residue waspurified on silica gel using hexanes as eluent to give product. (107 mg,63%).

Step B: Benzyl4-(7-(5-methyl-1-(triisopropylsilyl)-1H-indol-4-yl-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:A stirred mixture of tris(dibenzylideneacetone)dipalladium (0) (17 mg,0.019 mmol) and (+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (24mg, 0.038 mmol) in dry degassed toluene (0.5 mL) under nitrogen washeated to 100° C. for 15 minutes. The mixture was cooled to roomtemperature and solid sodium-t-butoxide (37 mg, 0.38 mmol) addedfollowed by addition of a solution of4-bromo-5-methyl-1-(triisopropylsilyl)-1H-indole (90 mg, 0.25 mmol) andbenzyl4-(2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(94 mg, 0.19 mmol) in dry degassed toluene (0.5 mL). The reaction flaskwas closed and heated to 100° C. overnight. The reaction mixture wascooled to room temperature, divided between EtOAc (15 mL) and water (5mL) and the layers separated. The organic layer was washed with brine,dried over Na₂SO₄ and evaporated in vacuo. The product was purified bychromatography on silica gel, Redisep 24 g, using 3 to 5% MeOH indichloromethane as eluent to give a light-yellow solid (28 mg, 19%).ES+APCI MS m/z 782.3 [M]⁺.

Step C:1-(4-(7-(5-methyl-1H-indol-4-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one:A mixture of benzyl4-(7-(5-methyl-1-(triisopropylsilyl)-1H-indol-4-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(46 mg, 0.065 mmol), palladium on carbon (35 mg, Degussa Type, 10 wt %,50% H₂O) in EtOH (1 mL) and THF (1 mL) was purged with hydrogen andstirred under H₂ atmosphere (rubber balloon) overnight. The reactionmixture was diluted with dioxane (3 mL), filtered through celite and thecelite washed with dioxane (2×2 mL). The combined organics wereevaporated in vacuo and dried under high vacuum. The residue wasdissolved in THF (1 mL) under N₂, then 1M tetra-n-butylammonium fluoridein THF (0.07 mL, 2 eq.) was added with stirring and the solution stirredat 0° C. for 15 minutes. The reaction mixture was divided between ether(15 mL) and water (5 mL) and the layers separated. The organic layer waswashed with water (3 mL), brine (3 mL), dried over Na₂SO₄ and evaporatedunder nitrogen. The crude product was dissolved in DCM (3 mL) and cooledin an ice-salt-dry ice bath (−20° C.) with stirring. Triethylamine (10μL, 2 eq.) was next added followed by acryloyl chloride (2 μL, 0.75eq.). After 10 min at −20° C. the reaction was quenched with NH₄OH (0.03mL), and evaporated in vacuo. The product was purified by chromatographyon silica gel column using 5% MeOH/DCM+0.1% NH₄OH as eluent to give acolorless solid (3.69 mg, 19%). ES+APCI MS m/z 546.3 [M+H]⁺.

Example 2102-(1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: tert-butyl2-chloro-4-(3-(cyanomethyl)piperazin-1-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:tert-butyl2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (8.00g, 26.3 mmol), Hunig's base (22.9 ml, 132 mmol) and2-(piperazin-2-yl)acetonitrile dihydrochloride (5.21 g, 26.3 mmol) wereplaced in DMA (75 mL) and stirred at room temperature for 20 minutes.Water was added to the reaction and the mixture was extracted with EtOAc(3×100 mL). The extracts were combined and washed with water (3×50 mL),dried with sodium sulfate, filtered and concentrated to provide crudematerial that was used as is. ES+APCI MS m/z 393.3 [M+H]⁺.

Step B: tert-butyl4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:tert-butyl2-chloro-4-(3-(cyanomethyl)piperazin-1-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(10.5 g, 26.7 mmol) and TEA (5.6 ml, 40.1 mmol) were placed in THF (100mL) and cooled to 0° C. Benzyl carbonochloridate (5.7 ml, 40.1 mmol) wasadded and the reaction was stirred at 0° C. for 30 minutes. Water wasadded to the reaction and the mixture was extracted with DCM (3×50 mL)and the extracts were combined and concentrated. The residue waspurified by silica gel (0-60% EtOAc in hexane as eluent) to providetert-butyl4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(12.9 g, 24.5 mmol, 92% yield). ES+APCI MS m/z 527.1 [M+H]⁺.

Step C: tert-butyl4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:In a sealed tube tert-butyl4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(1.50 g, 2.85 mmol) was dissolved in dioxane (1.42 ml, 2.85 mmol) andtreated with milled cesium carbonate (1.85 g, 5.69 mmol) and(2S)-1-Ethyl-2-pyrrolidinyl]methanol (1.64 g, 14.2 mmol). The tube wasthen capped and heated to 90° C. for 24 hr. The reaction was cooled toroom temperature and water was added. The mixture was extracted with DCM(3×25 mL), and the combined organics concentrated in vacuo. The residuewas purified by silica gel (0-12% MeOH in DCM w/0.2% NH4OH as eluent) togive tert-butyl4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(831 mg, 1.37 mmol, 48% yield). ES+APCI MS m/z 606.2 [M+H]⁺.

Step D: benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:tert-butyl4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(831 mg, 1.37 mmol) was placed in DCM (15 mL) and TFA (2114 μL, 27.4mmol) was added and the reaction was stirred at rt for 1 hr. Thereaction was concentrated Saturated bicarbonate was added and themixture was extracted with DCM (3×25 mL). The extracts were combined,dried with sodium sulfate, filtered and concentrated to give benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(665 mg, 1.32 mmol, 96% yield) which was used as is. ES+APCI MS m/z506.2 [M+H]⁺.

Step E: benzyl2-(cyanomethyl)-4-(2-(((S1-methylpyrrolidin-2-yl)methoxy-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:To a vial was added cesium carbonate (103 mg, 0.316 mmol), benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(80 mg, 0.158 mmol), Rhuphos Pd G3 (13.2 mg, 0.016 mmol),1-bromo-2-(trifluoromethyl)benzene (53.4 mg, 0.237 mmol) and 1,4-dioxane(1582 μL, 0.158 mmol) and the vial was degassed with Ar, sealed thenheated to 70° C. for 24 hours. Water and saturated NH4Cl were added tothe reaction and the mixture was extracted with DCM. The organic layerconcentrated in vacuo. The resulting residue was purified by silica gel(0-12% MeOH in DCM w/0.2% NH4OH as eluent) to provide benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(20.5 mg, 0.032 mmol, 20% yield). ES+APCI MS m/z 650.3 [M+H]⁺.

Step F:2-(4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(2-(trifluoromethyl)phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:To a solution of benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(20.5 mg, 0.032 mmol) in EtOH (316 μL, 0.0316 mmol) and THF (316 μL,0.032 mmol) was added palladium (16.8 mg, 0.008 mmol) (Degussa Type, 10wt %, 50% H2O) and then an atmosphere of H2 was introduced via vacuumfollowed by balloon pressure and was stirred for 2 hours. The mixturewas then diluted with MeOH and filtered through GF/F paper. The filtratewas then concentrated to provide desired product which was used as is.ES+APCI MS m/z 516.2 [M+H]⁺.

Step G:2-(1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(2-(trifluoromethylphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-ylacetonitrile:2-(4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(16.3 mg, 0.032 mmol) and triethylamine (13.2 μL, 0.095 mmol) wereplaced in CH2Cl2 (316 μL, 0.032 mmol) and cooled to 0° C. Acryloylchloride (632 μL, 0.063 mmol) was added (freshly prepared 0.1M solutionin DCM) and the reaction was stirred for 1 hour at 0° C. The mixture wasconcentrated and the resulting residue was purified by reverse phasechromatography (0-50% ACN:water w/0.1% TFA) to provide desired product(18.9 mg, 0.027 mmol, 87% yield). ES+APCI MS m/z 570.3 [M+H]⁺.

Example 2112-(1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(2-(trifluoromethoxy)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Synthesized according to Example 210, Steps E-G using1-bromo-2-(trifluoromethoxy)benzene in place of1-bromo-2-(trifluoromethyl)benzene in Step E. ES+APCI MS m/z 586.3[M+H]⁺.

Example 2122-(1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(4-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Synthesized according Example 210, Steps E-G using3-bromo-4-(trifluoromethyl)pyridine in place of1-bromo-2-(trifluoromethyl)benzene in Step E. ES+APCI MS m/z 571.3[M+H]⁺.

Example 2131-(4-(7-(5-hydroxy-2,3-dimethylphenyl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: 3-bromo-4,5-dimethylphenol: In a sealed tube DPPE (0.431 g, 1.08mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.73 g, 13.5 mmol),(1,5-Cyclooctadiene)-eta5-indenyl)iridium(I) (0.449 g, 1.08 mmol) and1-bromo-2,3-dimethylbenzene (1.00 g, 5.40 mmol) were placed incyclohexane (6 mL) and was heated to 100° C. for 50 hr. The reaction wasconcentrated down and brought up in acetone (5 mL) and oxzone (3.32 g,5.40 mmol) was added and stirred for 10 min. The reaction was quenchedwith saturated NaHSO₃ and was extracted with DCM (3×20 mL). The extractswere washed with brine, water and concentrated. The residue was passedthrough a plug of silica eluting with DCM to provide3-bromo-4,5-dimethylphenol (238 mg, 1.18 mmol, 22% yield).

Step B: 1-bromo-5-(methoxymethoxy)-2,3-dimethylbenzene: Was preparedaccording to the preparation for Intermediate 3 substituting the3-bromo-4,5-dimethylphenol for 2-bromo-3-fluorophenol.

Step C:1-(4-(7-(5-hydroxy-2,3-dimethylphenyl-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one2,2,2-trifluoroacetate: was prepared according to Example 1 Steps C-Fsubstituting Intermediate 25 for benzyl4-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylateand 1-bromo-5-(methoxymethoxy)-2,3-dimethylbenzene for1-bromo-3-(methoxymethoxy)naphthalene in Step C. ES+APCI MS m/z 537.3[M+H]⁺.

Example 2141-(4-(7-(5-hydroxy-2-((trifluoromethyl)thio)phenyl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: 3-bromo-4-((trifluoromethyl)thio)phenol: In a sealed tube3-bromophenol (575 mg, 3.32 mmol) andN,4-dimethyl-N-(trifluoromethyl)benzenesulfonamide (1010 mg, 3.99 mmol)were placed in dry DCE (6 mL). Triflic acid (295 μL, 3.32 mmol) wasadded slowly and the reaction was then heated to 80° C. for 18 hours.The reaction was cooled and the solvent was removed under vacuum and theresulting residue was purified by silica gel (0-20% EtOAc in hexanes) toprovide 3-bromo-4-((trifluoromethyl)thio)phenol (650 mg, 2.38 mmol, 72%yield)

Step B: (2-bromo-4-(methoxymethoxy)phenyl)(trifluoromethyl)sulfane: Wasprepared according to the preparation for Intermediate 3 substitutingthe 3-bromo-4-((trifluoromethyl)thio)phenol for 2-bromo-3-fluorophenol.

Step C:1-(4-(7-(5-hydroxy-2-((trifluoromethylthio)phenyl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one:Synthesized according to Example 1 Step C-F substituting Intermediate 25for benzyl4-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylateand (2-bromo-4-(methoxymethoxy)phenyl)trifluoromethyl)sulfane for1-bromo-3-(methoxymethoxy)naphthalene in Step C. ES+APCI MS m/z 609.2[M+H]⁺.

Example 215(R)-1-(4-(2-(2-hydroxy-3-morpholinopropoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Title compound was obtained by SFC chiral resolution of Example 123using a Phenomenex OZ-H column (4.6 mm×250 mm, 5 u) and eluting with40-60%. MeOH:IPA:DEA (80:20:1) at 4 mL/min. Collecting the first elutingpeak provided the desired compound where the stereochemistry wasarbitrarily assigned. ES+APCI MS m/z 575.2 [M+H]⁺.

Example 216(S)-1-(4-(2-(2-hydroxy-3-morpholinopropoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Title compound was obtained by SFC chiral resolution of Example 123using a Phenomenex OZ-H column (4.6 mm×250 mm, 5 u) and eluting with40-60% MeOH:IPA:DEA (80:20:1) at 4 mL/min. Collecting the second elutingpeak provided the desired compound where the stereochemistry wasarbitrarily assigned. ES+APCI MS m/z 575.2 [M+H]⁺.

Example 2171-(4-(2-((1-hydroxy-3-morpholinopropan-2-yl)oxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using3-morpholinopropane-1,2-diol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 575.2 [M+H]⁺.

Example 2182-(1-acryloyl-4-(2-(((2S,4R)-4-hydroxy-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: benzyl4-(2-(((2S,4R)-1-(tert-butoxycarbonyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:In a sealed vial, a solution of benzyl4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(150 mg, 0.27 mmol) in dioxane (2712 μL, 0.27 mmol) was sparged withargon and(2S,4R)-4-{[tert-Butyl(dimethyl)silyl]oxy}-2-(hydroxymethyl)pyrrolidine-1-carboxylate(270 mg, 0.81 mmol), Cs2CO3 (265 mg, 0.81 mmol), Rhuphos Pd G3 (22.7 mg,0.027 mmol) were sequentially added under argon and sparged for anadditional 5 min. The reaction mixture was capped and heated at 100° C.for 2 hr. Water was added and the mixture was extracted with DCM (3×15mL). The extracts were combined and concentrated and the resultingresidue was purified by silica gel (0-40% EtOAc in hexanes) to providebenzyl4-(2-(((2S,4R)-1-(tert-butoxycarbonyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(113 mg, 0.13 mmol, 49% yield).

Step B: tert-butyl(2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(((4-(3-(cyanomethyl)piperazin-1-yl-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)pyrrolidine-1-carboxylate:To a solution of benzyl4-(2-(((2S,4R)-1-(tert-butoxycarbonyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(113 mg, 0.133 mmol) in EtOH (1.3 mL, 0.133 mmol) and THF (1.3 ml, 0.133mmol) was added palladium (70.9 mg, 0.033 mmol) (Degussa Type, 10 wt %,50% H2O) and then an atmosphere of H2 was introduced via vacuum followedby balloon pressure. The mixture was then stirred at ambient temperaturefor 2 hours. The mixture was then diluted with 1:1 MeOH and THF andfiltered through GF/F paper. The filtrate was then concentrated toprovide crude product which was used as is.

Step C: tert-butyl(2S,4R)-2-(((4-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yloxy)methyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate:tert-butyl(2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(((4-(3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)pyrrolidine-1-carboxylate(95 mg, 0.13 mmol) and triethylamine (56 μL, 0.40 mmol) were placed inCH2Cl2 (1331 μL, 0.13 mmol) and cooled to 0° C. Acryloyl chloride (2661μL, 0.27 mmol) (freshly prepared 0.1M solution in DCM) was added and thereaction was stirred for 30 min at 0° C. Water was added to the reactionand the mixture was extracted with DCM (3×15 mL). The extracts werecombined and concentrated to provide crude material which was used asis.

Step D:2-(1-acryloyl-4-(2-(((2S,4R)-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.tert-butyl(2S,4R)-2-(((4-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate(92 mg, 0.12 mmol) was placed in DCM (3 mL) and TFA (92 μL, 1.2 mmol)was added and the reaction was stirred at room temperature for 2 hours.Saturated bicarbonate was added to the reaction and the mixture wasextracted with DCM (3×15 mL). The extracts were combined, dried withsodium sulfate, filtered and concentrated to give crude material thatwas used as is.

Step E:2-(1-acryloyl-4-(2-(((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:2-(1-acryloyl-4-(2-(((2S,4R)-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(80 mg, 0.12 mmol), formaldehyde (45.0 μL, 0.60 mmol) and Na(OAc)3BH(50.8 mg, 0.24 mmol) were placed in THF (2 mL) and stirred for 2 hrs.Saturated bicarbonate was added and the mixture was extracted with 10%MeOH in DCM (3×15 mL). The extracts were combined, dried with sodiumsulfate, and concentrated to provide crude material which was used asis.

Step F:2-(1-acryloyl-4-(2-(((2S,4R)-4-hydroxy-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile2,2,2-trifluoroacetate:2-(1-acryloyl-4-(2-(((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(81 mg, 0.119 mmol) was placed in DCM (5 mL) and HCl (594 μL, 2.38 mmol)was added and the reaction was stirred for 1 hr. The reaction wasconcentrated and the material was purified by reverse phasechromatography (0-50% ACN:water with 0.1% TFA) to provide2-(1-acryloyl-4-(2-(((2S,4R)-4-hydroxy-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(38.9 mg, 0.057 mmol, 48% yield). ES+APCI MS m/z 568.3 [M+H]⁺.

Example 2191-(4(2-((1,4-dimethylpiperazin-2-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Title compound was prepared the same as Example 127, substituting(1,4-Dimethyl-2-piperazinyl)methanol in place of N-Methyl-L-prolinol inStep D. ES+APCI MS m/z 558.3 [M+H]⁺.

Example 2202-(1-acryloyl-4-(2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: benzyl4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate.To a solution of tert-butyl4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(4.00 g, 7.59 mmol) in DCM (25.3 ml, 7.59 mmol) was addedtrifluoroacetic acid (17.4 ml, 227.7 mmol) and the reaction was stirredat room temperature for 3 hours. The reaction was concentrated to athick oil. Saturated bicarbonate was added slowly and the mixture wasextracted with 10% MeOH in DCM (3×50 mL). The extracts were combined,dried with sodium sulfate and concentrated to provide the desiredproduct (3.24 g, 7.6 mmol, 100% yield) which was used as is. ES+APCI MSm/z 506.2 [M]⁺.

Step B: benzyl4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl-2-(cyanomethyl)piperazine-1-carboxylate:To a round bottomed flask was added cesium carbonate (8.01 g, 24.6mmol), benzyl4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(3.5 g, 8.2 mmol), 1-bromonaphthalene (4.6 ml, 32.8 mmol) and RuPhos PdG3 (1.0 g, 1.23 mmol). After evacuating the flask, 1,4-dioxane (82.0 ml,8.20 mmol) was added through a septum under argon flow. Argon wasbubbled through the mixture for 5 minutes and then the mixture washeated to 70° C. overnight. The reaction was cooled and water was addedand extracted with ethyl acetate and the organics concentrated in vacuo.The yellow solids were dissolved in minimal DCM and purified by silicachromatography (25-60% EtOAc in hexanes) to provide benzyl4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(2.0 g, 3.6 mmol, 44.1% yield). ES+APCI MS m/z 553.2 [M]⁺.

Step C: benzyl4-(2-((2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl-2-(cyanomethyl)piperazine-1-carboxylate:In a vial benzyl4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(120 mg, 0.22 mmol) was dissolved in dioxane (108 μL, 0.217 mmol) andtreated with cesium carbonate (141 mg, 0.434 mmol), and(2S,4R)-1-(tert-Butoxycarbonyl)-4-fluoro-2-hydroxymethylpyrrolidine(47.6 mg, 0.217 mmol). The tube was then capped and heated to 90° C. for12 hours. The reaction was filtered through GF/F paper and concentrated.The residue was purified by silica chromatography (0-6% MeOH in DCM).ES+APCI MS m/z 736.3 [M+H]⁺.

Step D: benzyl2-(cyanomethyl)-4-(2-((2S,4R)-4-fluoropyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylat:To a solution of benzyl4-(2-(((2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(125 mg, 0.170 mmol) in DCM (170 μL, 0.170 mmol) was addedtrifluoroacetic acid (195 μL, 2.55 mmol) and the reaction stirred at RTfor 2 hr. The organics were washed with sodium bicarbonate and theaqueous layer was back extracted with DCM. The combined organic layerswere concentrated and used without further purification. ES+APCI MS m/z636.3 [M+H]⁺.

Step E: benzyl2-(cyanomethyl)-4-(2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:To a solution of benzyl2-(cyanomethyl)-4-(2-(((2S,4R)-4-fluoropyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(105 mg, 0.1652 mmol) in DCE (3303 μL, 0.1652 mmol) was addedformaldehyde (124.1 μL, 1.652 mmol) (37% in water) followed by sodiumtriacetoxyborohydride (175.0 mg, 0.8258 mmol). The mixture was stirredvigorously at RT for 2.5 h. The mixture was treated with saturatedsodium bicarbonate (30 mL), stirred for 10 min then extracted with DCM(3×10 mL). The combined organic phases were dried over sodium sulfate,filtered and concentrated and used as is in the next reaction. ES+APCIMS m/z 650.3 [M+H]⁺.

Step F:2-(4-(2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:To a solution of benzyl2-(cyanomethyl)-4-(2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(85 mg, 0.13 mmol) in EtOH (1308 μL, 0.13 mmol) and THF (1308 μL, 0.13mmol) was added palladium (70 mg, 0.033 mmol) (Degussa Type, 10 wt %,50% H2O) and then an atmosphere of H₂ was introduced via vacuum followedby balloon pressure. The mixture was then stirred at ambient temperatureovernight. The mixture was then diluted with MeOH and filtered throughGF/F paper. The filtrate was then concentrated to provide2-(4-(2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.ES+APCI MS m/z 516.3 [M+H]⁺.

Step G:2-(1-acryloyl-4-(2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:To a suspension of2-(4-(2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(65 mg, 0.126 mmol) in DCM (1261 μL, 0.126 mmol) at 0° C. was addedacryloyl chloride (2521 μL, 0.252 mmol) (freshly prepared 0.1M solutionin DCM) followed by triethylamine (35.1 μL, 0.252 mmol). The reactionwas then stirred at 0° C. for 45 minutes. The reaction was concentratedand purified by reverse phase chromatography (0-50% CAN:water with 0.1%TFA) to provide the title compound. ES+APCI MS m/z 570.3 [M+H]⁺.

Example 2212-(1-acryloyl-4-(2-(((2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Synthesized according to the method of Example 220, Step C-G, usingtert-butyl (2S,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylatein place of tert-butyl(2S,4R)-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate in Step C.ES+APCI MS m/z 570.3 [M+H]⁺.

Example 2222-(1-acryloyl-4-(2-(((2S,4S)-4-methoxy-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was prepared following Example 220 (Steps C-G),substituting tert-butyl(2S,4S)-2-(hydroxymethyl)-4-methoxypyrrolidine-1-carboxylate for(2S,4R)-1-(tert-Butoxycarbonyl)-4-fluoro-2-hydroxymethylpyrrolidine inStep C. ES+APCI MS m/z 582.3 [M+H]⁺.

Example 2232-(1-acryloyl-4-(2-(((S)-4-methylpiperazin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Steps A-F:2-(1-acryloyl-4-(2-(((S)-4-methylpiperazin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:Title compound was prepared following Example 220 (Steps C-G),substituting tert-butyl(S)-2-(hydroxymethyl)-4-methylpiperazine-1-carboxylate for(2S,4R)-1-(tert-Butoxycarbonyl)-4-fluoro-2-hydroxymethylpyrrolidine inStep C. ES+APCI MS m/z 567.3 [M+H]⁺.

Example 2242-(1-acryloyl-4-(2-(((R)-4-methylpiperazin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was prepared following Example 220 (Steps C-G),substituting tert-butyl(R)-2-(hydroxymethyl)-4-methylpiperazine-1-carboxylate for tert-butyl(S)-2-(hydroxymethyl)-4-methylpiperazine-1-carboxylate in Step C.ES+APCI MS m/z 567.3 [M+H]⁺.

Example 2252-(1-acryloyl-4-(7-(5-fluoro-2-(trifluoromethoxy)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was prepared as in Example 210 Steps E-G, substituting2-bromo-4-fluoro-1-(trifluoromethoxy)benzene for1-bromo-2-(trifluoromethyl)benzene in step E. ES+APCI MS m/z 604.3[M+H]⁺.

Example 2262-(1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(2-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was prepared as in Example 210 Steps E-G, substituting3-bromo-2-(trifluoromethyl)pyridine for1-bromo-2-(trifluoromethyl)benzene in Step E. ES+APCI MS m/z 571.3[M+H]⁺.

Example 2272-(1-acryloyl-4-(7-(2-fluorophenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was prepared as in Example 210 Steps E-G, substituting1-bromo-2-fluorobenzene for 1-bromo-2-(trifluoromethyl)benzene in stepE. ES+APCI MS m/z 520.3 [M+H]⁺.

Example 2282-(1-acryloyl-4-(7-(2,3-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was prepared as in Example 210 Steps E-G, substituting1-bromo-2,3-dimethylbenzene for 1-bromo-2-(trifluoromethyl)benzene inStep E. ES+APCI MS m/z 530.3 [M+H]⁺.

Example 2292-(1-acryloyl-4-(7-(2-chlorophenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was prepared as in Example 210 Steps E-G, substituting1-bromo-2-chlorobenzene for 1-bromo-2-(trifluoromethyl)benzene in stepE. ES+APCI MS m/z 536.2 [M]+.

Example 2302-(1-acryloyl-4-(7-(3-fluoro-2-(trifluoromethyl)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was prepared as in Example 210 Steps E-G, substituting1-bromo-3-fluoro-2-(trifluoromethyl)benzene for1-bromo-2-(trifluoromethyl)benzene in Step E. ES+APCI MS m/z 588.3[M+H]+.

Example 2312-(1-acryloyl-4-(2-(3-hydroxypropoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: benzyl2-(cyanomethyl)-4-(2-(3-hydroxypropoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:Title compound was prepared as in Example 220 Step C, substitutingpropane-1,3-diol for(2S,4R)-1-(tert-Butoxycarbonyl)-4-fluoro-2-hydroxymethylpyrrolidine.ES+APCI MS m/z 593.3 [M+H]⁺.

Step 1: benzyl4-(2-(3-((tert-butyldimethylsilyl)oxy)propoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:To a vial was added benzyl2-(cyanomethyl)-4-(2-(3-hydroxypropoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(77.6 mg, 0.131 mmol), which was dissolved in DCM (655 μL, 0.131 mmol).The mixture was cooled to 0° C. and then triethylamine (36.5 μL, 0.262mmol) was added followed by 4-(dimethylamino)-pyridine (4.80 mg, 0.04mmol). Then tert-butyldimethylsilyl chloride (29.6 mg, 0.196 mmol) wasadded and the mixture was stirred overnight while warming to roomtemperature. The reaction mixture was poured onto a saturated brinesolution (5 mL) and the mixture extracted twice with EtOAc (10 mL). Theorganic phases were dried over sodium sulfate, filtered andconcentrated. The crude reaction product was used as is. ES+APCI MS m/z707.4 [M+H]+.

Step C:2-(4-(2-(3-((tert-butyldimethylsilyl)oxy)propoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:To a solution of benzyl4-(2-(3-((tert-butyldimethylsilyl)oxy)propoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(106 mg, 0.150 mmol) in EtOH (1499 μL, 0.150 mmol) and THF (1499 μL,0.150 mmol) was added palladium (79.8 mg, 0.0375 mmol) (Degussa Type, 10wt %, 50% H2O) and then an atmosphere of H₂ was introduced via vacuumfollowed by balloon pressure. The mixture was then stirred at ambienttemperature overnight. The mixture was then diluted with MeOH andfiltered through GF/F paper. The filtrate was then concentrated to acolorless solid that was used without further purification. ES+APCI MSm/z 573.3 [M+H]+.

Step D:2-(1-acryloyl-4-(2-(3-((tert-butyldimethylsilyl)oxy)propoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:To a suspension of2-(4-(2-(3-((tert-butyldimethylsilyl)oxy)propoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(75 mg, 0.131 mmol) in DCM (1309 μL, 0.131 mmol) at −78° C. was addedacryloyl chloride (2619 μL, 0.262 mmol) (freshly prepared 0.1M solutionin DCM) followed by triethylamine (36.5 μL, 0.262 mmol). The reactionwas then stirred at 0° C. for 30 minutes. The reaction was concentratedand used crude in the next reaction. ES+APCI MS m/z 627.4 [M+H]+.

Step E:2-(1-acryloyl-4-(2-(3-hydroxypropoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:To a solution of2-(1-acryloyl-4-(2-(3-((tert-butyldimethylsilyl)oxy)propoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(90 mg, 0.14 mmol) in DCM (1436 μL, 0.14 mmol) was added hydrochloricacid (4.0 M in 1,4-dioxane)(359 μL, 1.4 mmol) at 0° C. The reaction wasstirred for 30 min at which point it was quenched with saturated sodiumbicarbonate and extracted into 10% IPA in CHCl3 (3×15 mL). The combinedorganic layers were concentrated and the residue was purified by reversephase chromatography (0-95% ACN:H2O with 0.1 TFA). ES+APCI MS m/z 513.2[M+H]+.

Example 2321-(4-(7-(3-chloro-2-fluoro-5-hydroxyphenyl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

The title compound was prepared according to Example 1 Step C-Fsubstituting Intermediate 25 for benzyl4-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylateand 1-bromo-3-chloro-2-fluoro-5-(methoxymethoxy)benzene for1-bromo-3-(methoxymethoxy)naphthalene in Step C. ES+APCI MS m/z 561.2[M]+.

Example 2332-(1-acryloyl-4-(2-(((S)-1-ethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-(1-acryloyl-4-(2-(((S)-1-ethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-ylacetonitrile. This compound was prepared following Example 147substituting (S)-(1-ethylpyrrolidin-2-yl)methanol forN-Methyl-L-prolinol for [(2S)-1-methylpyrrolidin-2-yl]methanol in StepF. ES+APCI MS m/z 566.3 [M+H]⁺.

Example 2342-((S)-1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: 1-Benzyl 4-(tert-butyl)(R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate: To a stirred biphasicsolution of (R)-1-Boc-3-hydroxymethylpiperazine (5.00 g, 23.1 mmol) andNaHCO₃ (5.83 g, 69.4 mmol) in ethyl acetate (46.2 mL) and water (46.2mL) at 0° C. was added benzyl chloroformate (4.95 ml, 34.7 mmol)dropwise. The reaction mixture was stirred at ambient temperatureovernight. The reaction mixture was diluted with EtOAc (50.0 mL) and theorganic layer was separated, dried (Na₂SO₄) and concentrated. The crudeproduct was purified by flash chromatography eluting with 10-50%EtOAc/hexanes gradient to afford the title compound (7.62 g, 21.7 mmol,94.1%). ESI MS m/z 251.1 [M-Boc+H]+.

Step B. 1-Benzyl4-tert-butyl)(R)-2-(methylsulfonyl)oxy)methyl)piperazine-1,4-dicarboxylate:To a solution of 1-benzyl 4-(tert-butyl)(R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate (1.69 g, 4.83 mmol)and triethylamine (1.01 ml, 7.25 mmol) in CH₂Cl₂ (32.2 mL) at 0° C. wasadded dropwise MsCl (0.561 ml, 7.25 mmol) neat and the resulting mixturewas stirred at RT for 10 min. The reaction mixture was poured into aseparatory funnel, diluted with ethyl acetate, then washed sequentiallywith 1N HCl, water, NaHCO₃ (sat.), and brine to afford the titlecompound (1.9 g, ˜100%, used as crude material in next step). ESI MS m/z329.1 [M−Boc+H]+.

Step C: 1-Benzyl4-(tert-butyl)(S)-2-(cyanomethyl)piperazine-1,4-dicarboxylate: Asolution of 1-benzyl 4-(tert-butyl)(R)-2-((methylsulfonyl)oxy)methyl)piperazine-1,4-dicarboxylate (2.10 g,4.90 mmol), sodium cyanide (0.480 g, 9.80 mmol) in DMA (49.0 mL) washeated at 55° C. for 1 day. The reaction was followed by HPLC (15 minmethod). The mixture was partitioned between EtOAc/brine, and theorganic layer was washed with brine (3×), dried over MgSO₄ andconcentrated. The residue was purified by flash chromatography elutingwith 0-100% EtOAc/hexanes gradient to afford the title compound (1.40 g,3.90 mmol, 79.5%). Aqueous layers were basified and disposed of incyanide waste stream. ESI MS m/z 260.1 [M−Boc+H]+.

Step D. Benzyl (S)-2-(cyanomethyl)piperazine-1-carboxylatehydrochloride: 1-Benzyl4-(tert-butyl)(S)-2-(cyanomethyl)piperazine-1,4-dicarboxylate (5.32 g,14.8 mmol) was placed in CH₂Cl₂ (25 mL) and HCl (4.0 N in dioxane, 18.5ml, 74.0 mmol) was added and the reaction was stirred at ambienttemperature for 1 d. The reaction mixture was concentrated to afford thetitle compound (4.3 g, 99%). ESI MS m/z 260.1 [M+H]+.

Step E. tert-Butyl(S)-4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:A solution of benzyl (S)-2-(cyanomethyl)piperazine-1-carboxylate (1.01g, 3.89 mmol), tert-butyl2,4-dichloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (1.18g, 3.89 mmol) and DIEA (1.36 ml, 7.79 mmol) in DMSO (19.5 mL) was heatedat 50° C. for 1 day. The reaction mixture was partitioned between ethylacetate and brine and the organics separated. The organic phase waswashed with brine (3×), dried over MgSO₄ and concentrated to afford thetitle compound (1.63 g, 3.09 mmol, 79.4%) ESI MS m/z 527.2 [M+H]+.

Step F. tert-butyl4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:In 250 mL heavy-wall round bottom flask with a PTFE screw cap was addeda solution of tert-butyl(S)-4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(1.64 g, 3.11 mmol) in dioxane (31.1 mL) and the mixture was spargedwith argon. To the mixture was added sequentially(S)-(1-methylpyrrolidin-2-yl)methanol (1.08 g, 9.34 mmol), Cs₂CO₃ (3.04g, 9.34 mmol) and Ruphos-Pd Gen3 catalyst (0.260 g, 0.311 mmol) underargon and sparged for an additional 5 min. The reaction mixture wascapped and heated at 100° C. for 1 day. The reaction mixture was dilutedwith ethyl acetate and the organics washed with brine (2×). The organiclayer was dried over MgSO₄ and concentrated to give a residue that waspurified by flash chromatography eluting with 0-20% (MeOH+2% NH₄OH) inDCM to afford the title compound (1.42 g, 2.34 mmol, 75.3%). ESI MS m/z606.3 [M+H]+.

Step G. Benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatebis-trifluoroacetate salt: A solution of tert-butyl4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(38 mg, 0.063 mmol) in CH₂Cl₂ (627 μl) and TFA (242 μl, 3.1 mmol) wasstirred at room temperature for 1 day. The reaction mixture wasconcentrated and used as bis-TFA salt in the next reaction (46 mg, 0.063mmol, 100%). ESI MS m/z 506.3 [M+H]+.

Step H. Benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:A suspension of benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatebistrifluoracetate salt (46 mg, 0.063 mmol), 1-bromonaphthalene (39.3mg, 0.190 mmol) and Cs₂CO₃ (61.9 mg, 0.190 mmol) in dioxane (633 μl) wassparged with argon for 5 min. To this mixture was added Ruphos Pd Gen 3(5.29 mg, 0.006 mmol) and the resulting suspension was sparged for anadditional 1 minute with argon. The vial was capped and heated at 100°C. for 2 h. The reaction mixture was partitioned between EtOAc and waterand the aqueous layer was extracted with EtOAc (3×). The combinedorganic layers were dried over MgSO4 and concentrated. The residue waspurified by flash chromatography eluting with 5% MeOH/1% NH₄OH/CH₂Cl₂isocratic to afford the title compound (31.9 mg, 0.050 mmol, 79.8%). ESIMS m/z 632.3 [M+H]+.

Step I.2-((S)-4-(2-(((S)-1-Methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:To a solution of benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(31 mg, 0.049 mmol) in methanol (981 μl) and THF (981 μl) sparged withnitrogen was added Pd/C (10.4 mg, 0.00491 mmol) and the mixture wasstirred under balloon pressure atmosphere of H₂ for 1 day. The reactionmixture was filtered through a PTFE syringe filter (25 mm) and thefiltrate was concentrated to afford the title compound (23.4 mg, 0.047mmol, 95.8%). ESI MS m/z 498.3 [M+H]+.

Step J.2-((S)-1-Acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:To a solution of2-((S)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(23.4 mg, 0.047 mmol) in CH₂Cl₂ (470 μl) was added DIEA (41.1 μl, 0.235mmol) then acryloyl chloride (12 μl, 0.141 mmol). The resulting mixturewas stirred at ambient temperature for 15 minutes. The reaction mixturewas partitioned between EtOAc and 2N K₂CO₃ and brine. The aqueous layerwas extracted with EtOAc (2×). The combined organic layers were driedover MgSO₄ and concentrated. The residue was purified by flashchromatography eluting with 5% MeOH/1% NH₄OH in CH₂Cl₂ to afford thetitle compound (19.2 mg, 0.035 mmol, 74.0%). ESI MS m/z 552.3 [M+H]+.

Example 2352-((S)-1-((E)-4-(dimethylamino)but-2-enoyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A:2-((S)-1-((E)-4-(dimethylamino)but-2-enoyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:To a solution of2-((S)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(25 mg, 0.0502 mmol) from Example 234 Step I,(2E)-4-(dimethylamino)but-2-enoic acid (13.0 mg, 0.100 mmol), DIEA (43.9μl, 0.251 mmol) in CH₂Cl₂ (502 μl) was added HATU (28.7 mg, 0.0754 mmol)and the resulting mixture was stirred at ambient temperature for 1 hour.The reaction mixture was partitioned between EtOAc and brine. Theaqueous layer was extracted with EtOAc (2×). The combined organic layerswere dried over MgSO₄ and concentrated. The residue was purified bypreparative-C18 eluting with 5-95% ACN/H₂O+0.1% TFA. The desiredfractions were partitioned between EA/2M K₂CO₃. The aqueous wasextracted with EtOAc (2×) The combined organic layers were dried overMgSO₄ and concentrated to afford the title compound (19.0 mg, 0.031mmol, 62.1%). ESI MS m/z 609.4 [M+H]+.

Example 2362-((S)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(E-4-(piperidin-1-yl)but-2-enoyl)piperazin-2-yl)acetonitrile

Step A.2-((S)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(E-4-(piperidin-1-yl)but-2-enoyl)piperazin-2-yl)acetonitrilewas prepared according to Example 235, substituting(2E)-4-(1-piperidinyl)-2-butenoic acid HCl salt, to afford the titlecompound (30 mg, 0.046 mmol, 92.0%). ESI MS m/z 649.3 [M+H]+.

Example 2372-((S)-1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile2,2,2-trifluoroacetate

Synthesized according to Example 234 substituting1-bromo-2-(trifluoromethyl)benzene for 1-bromonaphthalene. ES+APCI MSm/z 570.3 [M+H]⁺.

Example 2382-(1-acryloyl-4-(7-(6-methyl-1H-indazol-7-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A:7-bromo-6-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole. Asolution of 7-bromo-6-methyl-1H-indazole (200 mg, 0.948 mmol) intetrahydrofuran (2 ml, 0.948 mmol) was cooled with stirring in an icebath. Sodium hydride (45.5 mg, 1.14 mmol) was added portionwise to themixture and the reaction was stirred at 0° C. for 1 hour.(2-(chloromethoxy)ethyl)trimethylsilane (0.201 ml, 1.14 mmol) was nextadded and the reaction stirred for 2 hours while warming to roomtemperature. The mixture was divided between EtOAc (20 mL) and water (10mL) and the layers separated. The organic layer was washed with water(2×10 mL), brine (10 mL), dried over Na₂SO₄ and evaporated in vacuo. Theproduct was purified by chromatography on silica gel using 20 to 40%EtOAc/hexanes as eluent to give7-bromo-6-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (46mg, 14%) along with isomer7-bromo-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (214mg, 66%). ES+APCI MS m/z 341.1 [M]⁺.

Step B: Benzyl2-(cyanomethyl)-4-(7-(6-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:A mixture of benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(50 mg, 0.099 mmol),7-bromo-6-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (46mg, 0.13 mmol), Cs₂CO₁ (97 mg, 0.30 mmol), Ruphos Pd G3 (83 mg, 0.099mmol) and dioxane (1 mL) was purged with nitrogen and stirred at 70° C.for 6 hours. The reaction mixture was cooled to room temperature anddivided between EtOAc (20 mL) and water (10 mL) and the layersseparated. The organic layer was washed with water (5 mL), brine (5 mL),dried over Na₂SO₄ and evaporated in vacuo. The product was purified bychromatography on silica gel, Redisep 24 g, using 2 to 20% MeOH/DCM aseluent to give a colorless solid (50 mg, 66%). ES+APCI MS m/z 766.4[M]⁺.

Step C: Benzyl2-(cyanomethyl)-4-(7-(6-methyl-1H-indazol-7-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:Neat benzyl2-(cyanomethyl)-4-(7-(6-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(10 mg, 0.0131 mmol) (10 mg, 0.0131 mmol) was dissolved intrifluoroacetic acid (1 ml, 13.1 mmol) and the yellow-brow solution wasstirred at room temperature for 1.5 hours. The reaction mixture waspoured into ethyl acetate (20 mL) and the organics washed carefully with2M Na₂CO₃ (10 mL, 20 mmol), water (2×3 mL), brine (5 mL), dried overNa₂SO₄ and evaporated in vacuo to give a yellowish solid (8 mg, 96%).ES+APCI MS m/z 636.3 [M+H]⁺.

Step D:2-(1-acryloyl-4-(7-(6-methyl-1H-indazol-7-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:A stirred mixture of benzyl2-(cyanomethyl)-4-(7-(6-methyl-1H-indazol-7-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(16 mg, 0.02517 mmol), methanol (1.5 ml, 0.02517 mmol), tetrahydrofuran(1.815 mg, 0.02517 mmol) and palladium on carbon (10 mg, 5%, Degussatype E101 NO/W) was degassed and stirred under hydrogen atmosphere for 1hour. The mixture was filtered through Celite (2 mL) and the celitewashed with THF (3×3 mL). The combined organics were concentrated invacuo to ˜0.5 mL, dissolved in DCM (5 mL), cooled to −30° C. withstirring in an EtOH-H₂O—CO₂ bath. Triethylamine (0.02 mL, 5 eq.) wasnext added followed by acryloyl chloride (0.006134 ml, 0.07550 mmol) andthe reaction mixture was stirred 1 min at −30° C. The reaction wasquenched with NH₄OH (0.03 mL) and concentrated in vacuo. The residue wasdivided between 1 M NaHCO₃ (3 mL) and EtOAc (15 mL) and the layersseparated. The organic layer was washed with water (3 mL), brine (3 mL),dried over Na₂SO₄ and evaporated in vacuo. The product was purified bychromatography on silica gel, Redisep 12 g, using 10 to 20%MeOH/DCM+0.2% NH₄OH as eluent to give a colorless solid (5.96 mg, 43%).ES+APCI MS m/z 556.3 [M+H]⁺.

Example 2392-(1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(3-(trifluoromethyl)pyridin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Synthesized according to Example 210, Steps E-G using4-Bromo-3-(trifluoromethyl)pyridine hydrobromide in place of1-bromo-2-(trifluoromethyl)benzene in Step E. ES+APCI MS m/z 571.3[M+H]⁺.

Example 2402-(1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(2-(2,2,2-trifluoroethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Synthesized according to Example 210, Steps E-G using1-bromo-2-(2,2,2-trifluoroethyl)benzene in place of1-bromo-2-(trifluoromethyl)benzene in Step E. ES+APCI MS m/z 584.3[M+H]⁺.

Example 241 benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(3-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

Step A: In a vial, benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(100 mg, 0.198 mmol) was dissolved in dioxane (98.9 μl, 0.198 mmol) andtreated with cesium carbonate (129 mg, 0.396 mmol), and2-Fluoro-3-(trifluoromethyl)pyridine (163 mg, 0.989 mmol) The tube wasthen capped and heated to 90° C. for 12 hr. Reaction was filteredthrough GF/F paper and concentrated. The residue was purified by silicachromatography (0-12% MeOH in DCM).

Step B: Synthesized according to Example 210, Steps F-G using benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(3-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatein place of benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatein Step F. ES+APCI MS m/z 571.3 [M+H]⁺.

Example 2422-(1-(but-2-ynoyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

At 0° C., to a 25 mL RBF containing N,N-dimethylformamide (603 μL, 0.06mmol) was added2-(4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(30 mg, 0.06 mmol) and triethylamine (12.2 mg, 0.12 mmol). The reactionmixture was vigorously stirred while 2-Butynoic acid (6.08 mg, 0.07mmol) was added in one portion. Next, 1-Propanephosphonic acid cyclicanhydride (26.9 μl, 0.09 mmol) was added to the stirring mixture. Thereaction was allowed to stir for 2 h at 0° C. Water was added and thereaction extracted with EtOAc (2×25 mL). The organic layers were washedwith saturated LiCl, NaCl, and water (10 mL each wash). Dried andconcentrated to a solid that was purified by reverse phase prep HPLC(5-95% ACN:H2O, with 0.1% TFA) to provide the title compound.

Example 2432-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1H-indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: tert-butyl2-(cyanomethyl)-4-[2-methylsulfanyl-7-[5-trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of tert-butyl2-(cyanomethyl)-4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(1.05 g, 2.60 mmol),2-[[4-bromo-5-(trifluoromethyl)indazol-1-yl]methoxy]ethyl-trimethyl-silane(1.13 g, 2.86 mol), RuPhos (484 mg, 1.04 mmol) and Cs₂CO₃ (2.11 g, 6.49mmol) in toluene (20 mL) was added Pd₂(dba)₃ (475 mg, 519 umol) underN₂, the suspension was degassed under vacuum and purged with N₂ severaltimes. The mixture was warmed to 90° C. and stirred at 90° C. for 7hours. The reaction mixture was filtered and the filter cake was washedwith EtOAc (3×20 mL). The combined organic layers were concentratedunder vacuum. The residue was purified by silica gel chromatography(PE:EA from 30:1 to 4:1) and then by reversed phase flash column (ACN:100%) to give tert-butyl2-(cyanomethyl)-4-[2-methylsulfanyl-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(850 mg, 1.12 mmol, 43.3% yield, 95.0% purity) as a yellow solid. ESI MSm/z 719.5 [M+H]⁺.

Step B: tert-butyl2-(cyanomethyl)-4-[2-methylsulfinyl-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of tert-butyl2-(cyanomethyl)-4-[2-methylsulfanyl-7-[5-trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(850 mg, 1.18 mmol) in DCM (17 mL) was added m-CPBA (240 mg, 1.18 mmol,85.0% purity) at 0° C. and stirred at 0° C. for 1 hour. The reactionmixture was quenched by saturated Na₂S₂O₃ (15 mL) at 0° C. andseparated, then diluted with water (10 mL) and extracted with EtOAc (30mL). The combined organic layers were dried over anhydrous Na₂SO₄filtered and concentrated under vacuum. The residue was purified byreversed phase flash column (ACN/Water (0.1% FA)=80%) to give tert-butyl2-(cyanomethyl)-4-[2-methylsulfinyl-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(730 mg, 944 umol, 79.8% yield, 95.0% purity) as yellow solid. ESI MSm/z 735.5 [M+H]⁺.

Step C: tert-butyl2-(cyanomethyl)-4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of tert-butyl2-(cyanomethyl)-4-[2-methylsulfinyl-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(300 mg, 408 umol) and [(2R)-1-methylpyrrolidin-2-yl]methanol (94.0 mg,816 umol) in toluene (6 mL) was added t-BuONa (58.8 mg, 612 umol) at 15°C. and stirred at 15° C. for 0.5 hour. To the mixture was added EtOAc(15 mL) and water (5 mL), then extracted with EtOAc (3×10 mL). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by reversed phaseflash column (ACN/Water (0.1% FA)=54%) to give tert-butyl2-(cyanomethyl)-4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(216 mg, 261 umol, 64.0% yield, 95.0% purity) as brown solid. ESI MS m/z786.6 [M+H]⁺.

Step D:2-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile:To a solution of tert-butyl2-(cyanomethyl)-4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(190 mg, 242 umol) and 2,6-dimethylpyridine (311 mg, 2.90 mmol, 338 uL)in DCM (4 mL) was added TMSOTf (645 mg, 2.90 mmol, 524 uL) at 0° C. andstirred at 20° C. for 1 hour. The reaction mixture was quenched by MeOH(1 mL), then concentrated under vacuum. The residue was purified byreversed phase flash column (ACN/Water (0.1% FA)=40%),2-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(85 mg, 123 umol, 50.8% yield, 99.0% purity) was obtained as a whitesolid. ESI MS m/z 686.5 [M+H]⁺.

Step E:2-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrileTo a solution of2-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(85.0 mg, 124 umol), DIEA (96.1 mg, 744 umol, 130 uL) in DCM (2 mL) wasadded prop-2-enoyl prop-2-enoate (23.4 mg, 186 umol) at 0° C. and themixture stirred at 20° C. for 1 hour. The reaction mixture was quenchedby water (2 mL). The resulting mixture was extracted with DCM (3×5 mL).The combined organic layers were dried over anhydrous Na₂SO₄, filteredand concentrated under vacuum The residue was purified by reversed phaseflash column (ACN/Water (0.1% FA)=48%) to give2-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(45 mg, 54.7 umol, 44.2% yield, 90.0% purity) as white solid. ¹H NMR(400 MHz, chloroform-d) δ=8.16 (s, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.52 (d,J=8.8 Hz, 1H), 6.59 (br s, 1H), 6.45-6.36 (m, 1H), 5.84 (br d, J=10.4Hz, 1H), 5.76 (s, 2H), 5.12 (s, 1H), 4.44-4.28 (m, 3H), 4.21-4.08 (m,2H), 3.98 (br d, J=12.0 Hz, 1H), 3.63-3.54 (m, 2H), 3.48-3.39 (m, 2H),3.32 (br s, 1H), 3.10 (br s, 2H), 2.99-2.86 (m, 2H), 2.80 (br s, 2H),2.73-2.58 (m, 2H), 2.49 (s, 3H), 2.28 (br s, 1H), 2.05 (br s, 1H), 1.77(br s, 4H), 0.94-0.88 (m, 2H), −0.04 (s, 9H).

Step F:2-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1H-indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrileTo a solution of2-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(45 mg, 60.8 umol) in DCM (0.15 mL) was added TFA (208 mg, 1.82 mmol,135 uL) and the mixture stirred at 20° C. for 1 hour. The reactionmixture was basified by saturated NaHCO₃ (2 mL) to pH=8. The resultingmixture was extracted with DCM:MeOH (10:1) (3×5 mL). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by prep-HPLC(column: Phenomenex Synergi C18 150*30 mm*4 um; mobile phase. [water(0.225% FA)-ACN]; B %: 10%-40%, 10.5 min) to give2-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1H-indazol-4yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(8.2 mg, 12.0 umol, 19.8% yield, 96.2% purity, FA) as yellow oil. ESI MSm/z 610.4 [M+H]⁺.

Example 2442-[4-[7-(8-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: tert-butyl2-(cyanomethyl)-4-[7-(8-isoquinolyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of tert-butyl2-(cyanomethyl)-4-[2-[(1-methylpyrrolidin-2-yl)methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(210 mg, 445 umol), 8-bromoisoquinoline (185 mg, 891 umol), RuPhos (41.6mg, 89.1 umol) and Cs₂CO₃ (435 mg, 1.34 mmol) in toluene (4.5 mL) wasadded Pd₂(dba)₃ (40.8 mg, 44.5 umol) under N₂. The suspension wasdegassed under vacuum and purged with N₂ several times. The mixture wasstirred under N₂ at 90° C. for 12 hours. The mixture was filtered andthe filter cake was washed with EtOAc (3×10 mL). The combined organiclayers were concentrated under vacuum. The residue was purified byreversed phase flash column (ACN/Water (0.1% FA)=20%) to give tert-butyl2-(cyanomethyl)-4-[7-(8-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(160 mg, 240 umol, 54.0% yield, 90.0% purity) as brown solid. ESI MS m/z599.4 [M+H]⁺.

Step B:2-[4-[7-(8-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile:A solution of tert-butyl2-(cyanomethyl)-4-[7-(8-isoquinolyl)-2-[[(2S)-1-methylpyrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(190 mg, 317 umol) and TFA (724 mg, 6.35 mmol, 470 uL) was stirred at20° C. for 1 hour. The reaction mixture was concentrated under vacuum togive2-[4-[7-(8-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(230 mg, crude, 2 TFA) as a brown oil.

Step C:2-[4-[7-(8-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile:To a solution of2-[4-[7-(8-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(230 mg, 316 umol, 2 TFA) and DIEA (409 mg, 3.17 mmol, 551 uL) in DCM (5mL) was added prop-2-enoyl prop-2-enoate (47.9 mg, 380 umol) at 0° C.,then the mixture was stirred at 20° C. for 1 hour. Water (5 mL) wasadded to the mixture. The resulting mixture was extracted with DCM (3×5mL). The combined organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated under vacuum. The residue was purified byprep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase:[water (0.225% FA)-ACN]; B %: 1%-20%, 10 min) to give2-[4-[7-(8-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(12.5 mg, 19.7 umol, 6.23% yield, 94.5% purity, FA) as yellow solid. ESIMS m/z 553.2 [M+H]⁺.

Example 2452-[4-[7-(7-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: (7-methyl-3,4-dihydronaphthalen-1-yl)trifluoromethanesulfonate:To a solution of 7-methyltetraline-1-one (2.00 g, 12.5 mmol) and DIPEA(4.84 g, 37.5 mmol, 6.52 mL) in DCM (30 mL) was added Tf₂O (5.28 g, 18.7mmol, 3.09 mL) dropwise at −5° C. The mixture was stirred at 20° C. for3 hours. Upon completion, the mixture was concentrated under vacuum. Theresidue was purified by silica gel chromatograph (PE/EA 1/0 to 100/1) togive (7-methyl-3,4-dihydronaphthalen-1-yl) trifluoromethanesulfonate(1.53 g, 4.45 mmol, 35.6% yield, 85.0% purity) as a yellow oil. ¹H NMR(400 MHz, chloroform-d) δ=7.17 (s, 1H), 7.11-7.05 (m, 2H), 6.01 (t,J=4.8 Hz, 1H), 2.83 (t, J=8.0 Hz, 2H), 2.50 (dt, J=4.8, 8.0 Hz, 2H),2.36 (s, 3H).

Step B: (7-methyl-1-naphthyl) trifluoromethanesulfonate: A mixture of(7-methyl-3,4-dihydronaphthalen-1-yl)trifluoro methanesulfonate (1.40 g,4.79 mmol) and DDQ (2.17 g, 958 mmol) in dioxane (28 mL) was stirred at105° C. for 12 hours. Upon completion, the mixture was concentratedunder vacuum. The residue was purified by silica gel chromatography(PE/E A 1/0 to 100/1) to give (7-methyl-1-naphthyl)trifluoromethanesulfonate (1.10 g, 3.41 mmol, 71.2% yield, 90.0% purity)as a yellow oil. ¹H NMR (400 MHz, chloroform-d) δ=7.87-7.79 (m, 3H),7.49-7.38 (m, 3H), 2.59 (s, 3H).

Step C: tert-butyl 4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate: A mixture of7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido [3,4-d]pyrimidine (10 g,34.0 mmol), 2-piperazin-2-ylacetonitrile (10.1 g, 51.0 mmol, 2 HCl) andDIEA (17.6 g, 136 mmol, 23.7 mL) in dioxane (100 mL) was stirred at 50°C. for 2 hours. Boc₂O (14.8 g, 68.0 mmol, 15.6 mL) was added and themixture was stirred at 50° C. for 2 hours. The mixture was concentratedunder vacuum and the residue was diluted with ethyl acetate (500 mL).The separated organic layer was washed with water (1×300 mL), brine(1×200 mL), dried over sodium sulfate, filtered and concentrated undervacuum. The residue was triturated with ethyl acetate (100 mL). Theprecipitate was filtered and the filtered cake was washed with ethylacetate (50 mL) and dried under vacuum to give a gray solid. Thefiltrate was concentrated under vacuum. The residue was purified bycolumn chromatography over silica gel (petroleum ether/ethyl acetate100/1 to 1/2). The desired fractions were collected and concentratedunder vacuum to give solid then combined with above solid to givetert-butyl 4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (15 g, 29.10mmol, 85.6% yield, 93.7% purity) as yellow solid. ESI MS m/z 483.1[M+H]⁺.

Step D:4-[7-benzyl-2-[(1-methylpyrrolidin-2-yl)methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate: To a solutionof [(2S)-1-methylpyrrolidin-2-yl]methanol (1.19 g, 10.4 mmol, 1.23 mL,2.5 eq) in THF (30.0 mL) was added NaH (331 mg, 8.28 mmol, 60% purity inmineral oil, 2.00 eq) at 0° C. and the mixture was stirred at 0° C. for0.5 h. tert-Butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(2.00 g, 4.14 mmol, 1.00 eq) was added into the mixture and the mixturewas stirred at 80° C. for 4 hours. The mixture was poured into ice water(100 mL) and extracted with ether acetate (3×150 mL). The organic layerswere washed with saturated sodium chloride solution (1×200 mL), driedover Na₂SO₄, filtered and concentrated under vacuum to give tert-butyl4-[7-benzyl-2-[(1-methylpyrrolidin-2-yl)methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate (2.86 g, crude)as a black oil which was used in the next step without furtherpurification. ESI MS m/z 562.3 [M+H].

Step E: tert-butyl2-(cyanomethyl)-4-[2-[(1-methylpyrrolidin-2-yl)methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:NH₃ was bubbled into methanol (70.0 mL) at −78° C. for 30 minutes.tert-Butyl4-[7-benzyl-2-[(1-methylpyrrolidin-2-yl)methoxy]-6,8-dihydro-5H-pyrido[3,4-d] pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate (2.00 g,crude) and Pd/C (0.20 g, 10% purity) were added into the mixture. Themixture was stirred at 40° C. for 24 hours under H₂ at 15 psi. Themixture was filtered and concentrated under vacuum. The residue waspurified by reverse phase flash [water (FA, 0.1%)/ancetonitrile]. Thedesired fractions were adjusted to pH>7 by saturated sodium bicarbonatesolution (5.00 mL) and the aqueous layer extracted with ether acetate(3×100 mL). The combined organic layers were washed with brine (1×100mL), dried over Na₂SO₄, filtered and concentrated under vacuum to givetert-butyl2-(cyanomethyl)-4-[2-[(1-methylpyrrolidin-2-yl)methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.40 g, 845 umol, two steps 29.4% yield) as a yellow solid. ESI MS m/z472.2 [M+H]⁺.

Step F: tert-butyl2-(cyanomethyl)-4-[2-[(1-methylpyrrolidin-2-yl)methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:A solution of tert-butyl2-(cyanomethyl)-4-[2-[(1-methylpyrrolidin-2-yl)methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(185 mg, 392 umol), (7-methyl-1-naphthyl) trifluoromethanesulfonate (159mg, 549 umol), Pd₂(dba)₃ (35.9 mg, 39.2 umol), RuPhos (36.6 mg, 78.5umol) and Cs₂CO₃ (320 mg, 981 umol) in toluene (30 mL) was de-gassedwith N₂ and then heated to 90° C. for 12 hours under N₂. Uponcompletion, the mixture was filtered and the filtrate was concentratedunder vacuum. The residue was purified by reversed-phase flash [water(0.1% NH₃·H₂O)/acetonitrile] to give tert-butyl2-(cyanomethyl)-4-[7-(7-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(180 mg, 283 umol, 72.1% yield, 96.1% purity) as a yellow solid. ESI MSm/z 612.6 [M+H]⁺.

Step G:2-[4-[7-(7-methyl-1-naphthyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile:A solution of tert-butyl2-(cyanomethyl)-4-[7-(7-methyl-1-naphthyl)-2-[[(2b)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(180 mg, 294 umol) in TFA (671 mg, 5.88 mmol, 436 uL) was stirred at 20°C. for 1 hour. Upon completion the mixture was concentrated under vacuumto give2-[4-[7-(7-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(0.37 g, crude, TFA) as a yellow oil which was used directly in the nextstep without further purification.

Step H:2-[4-[7-(7-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile:To a solution of 2-[4-[7-(7-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(189 mg, crude, TFA) and DIEA (976 mg, 7.55 mmol, 1.32 mL) in DCM (4 mL)was added prop-2-enoyl prop-2-enoate (38.1 mg, 302 umol) dropwise at 0°C. The mixture was stirred at 25° C. for 1 hour. Upon completion, thereaction was quenched with MeOH (0.5 mL), diluted with water (1 mL) andextracted with DCM (3×5 mL). The organic layers were dried over Na₂SO₄and concentrated under vacuum. The residue was purified by prep-HPLC(column: Phenomenex Synergi C18 150*30 mm*4 um; mobile phase: [water(0.225% FA)-ACN]; B % 15%-45%, 10.5 min) to give2-[4-[7-(7-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(13.2 mg, 21.3 umol, two steps 14.2% yield, 98.4% purity, FA) as ayellow solid. ESI MS m/z 566.5 [M+H]⁺.

Example 2462-[4-[7-(4-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Synthesized according to the method for Example 147 substituting1-bromo-4-fluoronaphthalene for 1-bromonaphthalene in step H. ESI MS m/z570.5 [M+H]⁺.

Example 2472-(1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(quinolin-8-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Synthesized according to the method for Example 147 substituting8-bromoquinoline for 1-bromonaphthalene in Step H. ESI MS m/z 553.2[M+H]⁺.

Example 248(S)-1-(4-(7-(5-isopropyl-1H-indazol-4-yl)-2-((I-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: 2-(2-bromo-4-fluoro-phenyl)propan-2-ol: To a solution of1-(2-bromo-4-fluoro-phenyl)ethanone (10 g, 46.1 mmol) in THF (100 mL)was added MeMgBr (in ether) (3 M, 46.08 mL) at −50° C. The mixture waswarmed up to 0° C. and stirred for 3 hours. The mixture was quenchedwith saturated aqueous ammonium chloride solution (1.0 mL) at −50° C.The mixture was warmed up to 15° C. and was then diluted with ethylacetate (0.500 mL). The separated organic layer was washed with water(1×500 mL) and brine (500 mL), dried over sodium sulfate, filtered andconcentrated under vacuum to give 2-(2-bromo-4-fluoro-phenyl)propan-2-ol(10 g, 36.5 mmol, 79.2% yield, 85% purity) as a colorless oil.

Step B: 2-bromo-4-fluoro-1-isopropyl-benzene: To a solution of2-(2-bromo-4-fluoro-phenyl)propan-2-ol (9 g, 38.6 mmol) indichloromethane (100 mL) was added Et₃SiH (8.98 g, 77.2 mmol, 12.3 mL)and TFA (65.1 g, 571 mmol, 42.3 mL). The mixture was stirred at 15° C.for 1 hour and then heated to 50° C. for 1 hour. The reaction mixturewas concentrated under vacuum and then diluted with ethyl acetate (100mL). The aqueous layer pH was adjusted to pH=7 by addition of saturatedNaHCO₃ aqueous solution and extracted with ethyl acetate (50 mL×3). Thecombined organic phase was washed with brine (30 mL), dried withanhydrous Na₂SO₄, filtered and concentrated under vacuum. The residuewas purified by silica gel chromatography (Petroleum ether/Ethylacetate=1/0 to 100/1). The desired fractions were collected andconcentrated under vacuum. 2-bromo-4-fluoro-1-isopropyl-benzene (7 g,32.2 mmol, 83.5% yield) was obtained as colorless oil. ¹H NMR (400 MHz,chloroform-d) δ=7.36-7.27 (m, 2H), 7.09-7.02 (m, 1H), 3.46-3.31 (m, 1H),1.28 (d, J=6.8 Hz, 6H).

Step C: 2-bromo-6-fluoro-3-isopopyl-benzaldehyde: To a mixture of2-bromo-4-fluoro-1-isopropyl-benzene (7 g, 32.2 mmol in THF (100 mL) wasadded LDA (2 M in toluene, 24.2 mL) at −70° C. under nitrogenatmosphere. The mixture was stirred for 0.5 hour, and then DMF (7.07 g,96.7 mmol, 7.44 mL) was added. The mixture was stirred at −70° C. for 2hours. The reaction was quenched with water (100 mL) and extracted withethyl acetate (2×100 mL). The combined organic layers were washed withbrine (50 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by column chromatography(SiO₂, PE\EA=1\0 to 10\1). The desired fractions were collected andconcentrated under vacuum to give2-bromo-6-fluoro-3-isopropyl-benzaldehyde (2.4 g, 9.79 mmol, 30.4%yield) as a yellow oil. ¹H NMR (400 MHz, chloroform-d) δ 10.41 (s, 1H),7.48 (dd, J=5.6, 8.8 Hz, 1H), 7.13 (t, J=9.2, 1H), 3.57-3.46 (m, 1H),1.26 (d, J=7.2 Hz, 6H).

Step D: 4-bromo-5-isopropyl-1H-indazole:2-bromo-6-fluoro-3-isopropyl-benzaldehyde (2.4 g, 9.79 mmol) in DMSO (3mL) was added N₂H₄·H₂O (15.4 g, 302 mmol, 15 mL, 98% purity) and themixture was heated to 110° C. and stirred for 16 hours. The reactionmixture was poured into H₂O (10 mL) and extracted with ethyl acetate (20mL×3). The organic phase was washed with brine (10 mL), dried overanhydrous Na₂SO₄ and concentrated under vacuum to give the residue. Theresidue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=1/0 to 5/1) to give 4-bromo-5-isopropyl-1H-indazole(650 mg, 2.72 mmol, 27.8% yield) as a yellow solid. ¹H NMR (400 MHz,chloroform-d) δ=10.24 (br s, 1H), 8.08 (d, J=0.8 Hz, 1H), 7.43 (d, J=8.8Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 3.56 (td, J=6.8, 13.6 Hz, 1H), 1.29 (d,J=6.8 Hz, 6H).

Step E: 4-bromo-5-isopropyl-1-tetrahydropyran-2-yl-indazole: To asolution of 3,4-dihydro-2H-pyran (457 mg, 5.44 mmol, 497 uL, 2 eq) indichloromethane (15 mL) was added TsOH·H₂O (51.7 mg, 271 umol) and4-bromo-5-isopropyl-1H-indazole (650 mg, 2.72 mmol). The mixture wasstirred at 20° C. for 3 hours. The reaction mixture was diluted withwater (20 mL) and extracted with ethyl acetate (20 mL×2). The combinedorganic layers were washed with brine (20 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=1/0 to 5/1) and further purificated by reversedphase flash [water (0.1% formic acid)/acetonitrile] to give4-bromo-5-isopropyl-1-tetrahydropyran-2-yl-indazole (170 mg, 494 umol,18.2% yield, 94% purity) as a yellow oil. ESI MS m/z 323.0 [M+H]⁺.

Step F: tert-butyl4-[7-(5-isopropyl-1-tetrahydropyran-2-yl)-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:A mixture of 4-bromo-5-isopropyl-1-tetrahydropyran-2-yl-indazole (136mg, 420 umol), tert-butyl4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(140 mg, 323 umol), RuPhos (15.1 mg, 32.4 umol), RuPhos-Pd-G2 (25.1 mg,32.4 umol) and t-BuONa (77.7 mg, 809 umol) in toluene (3 mL) wasdegassed and purged with N₂ 3 times and the mixture was stirred at 90°C. for 12 hours under N₂ atmosphere. The mixture was diluted with ethylacetate (20 mL) and washed with water (20 mL). The organic layers werewashed with brine (10 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give a residue. The residue was purified bycolumn chromatography (SiO2, DCM/MeOH 100/1 to 10/1) and the desiredfractions were collected and concentrated under vacuum to givetert-butyl4-[7-(5-isopropyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(70 mg, 96.5 umol, 29.8% yield, 93% purity) was as a yellow solid. ESIMS m/z 675.3 [M+H]⁺.

Step G:7-(5-isopropyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine:To a solution of tert-butyl4-[7-(5-isopropyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(40 mg, 59.3 umol) in dichloromethane (100 uL) was added TFA (101 mg,889 umol, 65.8 uL). The mixture was stirred at 25° C. for 1 hour. Themixture was concentrated under vacuum to give7-(5-isopropyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(42 mg, 58.4 umol, 98.6% yield, 2 TFA) as a brown oil which was used innext step directly without purification. ESI MS m/z 491.4 [M+H]⁺.

Step H:1-[4-[7(5-isopropyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a mixture of7-(5-isopropyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(42 mg, 58.4 umol) and DIEA (75.5 mg, 584 umol, 102 uL) indichloromethane (2 mL) was added a solution of prop-2-enoylprop-2-enoate (7.37 mg, 58.4 umol, 1 eq) in dichloromethane (1 mL) at−40° C. under nitrogen atmosphere. The mixture was stirred at −40° C.for 1 hour. The reaction was quenched by adding saturated NaHCO₃ (2 mL)aqueous solution. Then the mixture was poured into water (20 mL) andextracted with dichloromethane (20 mL 2). The combined organics weredried over sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by prep-HPLC (column: Luna C18 150*25 5 u; mobilephase: [water (0.225% FA)-ACN]; B %: 5%-38%, 10 min) to give1-[4-[7-(5-isopropyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(4.5 mg, 7.93 umol, 13.6% yield, 96% purity) as a yellow solid. ESI MSm/z 545.2 [MH]⁺.

Example 2491-[4-[7-(2-fluoro-3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: tert-butyl4-[7-(2-fluoro-3-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:A mixture of tert-butyl4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.50 g, 1.16 mmol), (2-fluoro-3-methoxy-1-naphthyl)trifluoromethanesulfonate (562 mg, 1.73 mmol), RuPhos (108 mg, 231umol), Pd₂(dba)₃ (106 mg, 116 umol) and t-BuONa (333 mg, 3.47 mmol) intoluene (7 mL) as stirred at 110° C. for 3 hours under nitrogenatmosphere. The mixture was cooled and the pH of the aqueous layeradjusted to 7 by addition of saturated sodium bicarbonate solution andthe aqueous layer extracted with ether acetate (3×20 mL). The combinedorganic layers were washed with saturated sodium chloride solution,dried over Na₂SO₄, filtered and concentrated under vacuum. The residuewas purified by column chromatography (SiO₂,dichloromethane/methanol=10/1) and the mixture was concentrated to givetert-butyl4-[7-(2-fluoro-3-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.20 g, 274 umol, 11.8% yield,) as a yellow solid. ESI MS m/z 607.0[M+H]⁺.

Step B:7-(2-fluoro-3-methoxy-1-naphthyl)-1-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine:A mixture tert-butyl4-[7-(2-fluoro-3-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.20 g, 330 umol) and TFA (564 mg, 4.94 mmol 366 uL) in dichloromethane(0.4 mL) was stirred at 10° C. for 1 hour. The mixture was concentratedunder vacuum to give7-(2-fluoro-3-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (205mg, crude) as a yellow oil which was used in the next step withoutfurther purification. ESI MS m/z 507.0 [M+H]⁺.

Step C:1-[4-[7(2-fluoro-3-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a solution of 7-(2-fluoro-3-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(0.20 g, crude) and TFA (399 mg, 3.95 mmol, 549 uL) in dichloromethane(5 mL) was added prop-2-enoyl prop-2-enoate (49.8 mg, 394 umol) at −40°C., then stirred at −40° C. for 0.5 h. The mixture was quenched withmethanol (0.10 mL) and concentrated under vacuum. The residue waspurified by reversed phase flash [water (0.1% TFA)/acetonitrile]. Theaqueous layer pH was to 7 by addition of saturated sodium bicarbonatesolution and the aqueous layer extracted with dichloromethane/methanol(10/1) (3×10 mL). The combined organic layers were washed with saturatedsodium chloride (1×5 mL), dried over Na₂SO₄, filtered and concentratedunder vacuum to give1-[4-[7-(2-fluoro-3-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(0.10 g, 174 umol, 44.1% yield) as a yellow oil. ESI MS m/z 561.5[M+H]⁺.

Step D:1-[4-[7-(2-fluoro-3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a solution of1-[4-[7-(2-fluoro-3-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(0.10 g, 174 umol) in dichloromethane (3 mL) was added BBr₃ (223 mg, 892umol, 85.9 uL) at −78° C. The mixture was stirred at −78° C. for 0.5 hand 0° C. for 2 hours. The mixture was concentrated under vacuum,diluted with dichloromethane (3 mL) and water and the aqueous layer pHadjusted to >7 by addition of saturated sodium bicarbonate solution at−78-0° C. The aqueous layer was next extracted with dichloromethane(3×5.00 mL). The combined organics were concentrated under vacuum. Theresidue was purified by column chromatography (Al₂O₃,dichloromethane/methanol=10/1) and the mixture was concentrated undervacuum. The residue was purified by prep-HPLC (column: Phenomenex Gemini150*25 mm*10 um; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B %:30%-60%, 3 min) and further purified by prep-HPLC (column Luna C18150*25 5 u; mobile phase: [water (0.225% FA)-ACN]; B %: 20%-50%, 10min). The desired fractions were collected and lyophilized to give1-[4-[7-(2-fluoro-3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(1.59 mg, 2.91 umol, 1.63% yield, 100% purity, FA) as a yellow solid.ESI MS m/z 547.2[M+H]⁺.

Example 250

1-[4-[7-(5-chloro-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: 4-bromo-5-chloro-1-tetrahydropyran-2-yl-indazole: To a solutionof 4-bromo-5-chloro-1H-indazole (100 mg, 432.0 umol) in DCM (3 mL) wasadded TsOH·H₂ (8.22 mg, 43.2 umol) and 3,4-dihydro-2H-pyran (72.7 mg,864 umol, 79.0 uL). The mixture was stirred at 20° C. for 2 hours. Thereaction was washed by water (20 mL) and the aqueous layer extractedwith ethyl acetate (20 mL×2). The combined organics were dried withNa₂SO₄ and the solvent removed under vacuum. The residue was purified bycolumn chromatography (SiO₂, Petroleum ether/Ethyl acetate=10:1) to give4-bromo-5-chloro-1-tetrahydropyran-2-yl-indazole (270 mg, 810 umol,93.8% yield) as a white solid. ESI MS m/z 547.2[M+H]⁺.

Step B:tert-butyl-4-[7-(5-chloro-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:A mixture of tert-butyl4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(123 mg, 284.4 umol), 4-bromo-5-chloro-1-tetrahydropyran-2-yl-indazole(135 mg, 427 umol), Pd₂(dba)₃ (26.0 mg, 28.4 umol), RuPhos (20.0 mg,42.9 umol) and Cs₂CO₃ (278 mg, 853 umol) in dioxane (10 mL) was degassedand purged with N₂ and then the mixture was stirred at 100° C. for 12hrs under N₂ atmosphere. The reaction was quenched by adding water (20mL). The mixture was extracted with ethyl acetate (20 mL×3). Thecombined organics were dried with Na₂SO₄ and the solvent wasconcentrated under vacuum. The residue was purified by columnchromatography (SiO₂, Ethyl acetate/MeOH=10/1) to givetert-butyl-4-[7-(5-chloro-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(130.0 mg, 188.4 umol, 66.3% yield) as a white solid. ESI MS m/z668.2[M+H]⁺.

Step C:7-(5-chloro-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine:To a solution of tert-butyl4-[7-(5-chloro-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(50.0 mg, 74.9 umol) in DCM (2 mL) was added TFA (1.95 mL). The mixturewas stirred at 20° C. for 1 hr. The organic solvent was removed undervacuum to give7-(5-chloro-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(40.0 mg, crude, 2 TFA) as a yellow oil which was used directly in thenext step without further purification. ESI MS m/z 483.4 [M+H]⁺.

Step D:1-[4-[7-(5-chloro-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a solution of7-(5-chloro-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(40.0 mg, 2 TFA) and DIEA (50 mg, 387 umol, 67.4 uL) in DCM (3 mL) wasadded dropwise acrylic anhydride (9.0 mg, 71.4 umol) under N₂atmosphere. The mixture was stirred at −70° C. for 15 mins. The reactionwas quenched by adding water (10 mL). The mixture was extracted withethyl acetate (10 mL×3). The organic layer was dried with Na₂SO₄ and thesolvent removed under vacuum. The residue was purified by prep-HPLC(column: Luna C18 150*25 5 u; mobile phase: [water (0.225% FA)-ACN]; B%: 10%-37%, 10 mins) and lyophilized to give1-[4-[7-(5-chloro-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(11.9 mg, 20.8 umol, two steps 27.3%, 100% e.e.) as a yellow solid. ESIMS m/z 537.2 [M+H]⁺.

Example 2512-(1-acryloyl-4-(2-(((S)-1,2-dimethylpyrrolidin-2-yl))methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: benzyl4-(2-(((S)-1-(tert-butoxycarbonyl)-2-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate.In a microwave tube benzyl4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(200 mg, 0.362 mmol) was dissolved in dioxane (181 μl, 0.362 mmol) andtreated with cesium carbonate (236 mg, 0.723 mmol) and (S)-tert-butyl2-(hydroxymethyl)-2-methylpyrrolidine-1-carboxylate (389 mg, 1.81 mmol).The tube was then capped and heated to 90° C. for 2 hours. LC/MS showedreaction completion. The reaction was cooled to room temperature andfiltered through GF/F paper. The filtrate was concentrated in vacuo andchromatagraphed on the Combi Flash (0%-10% DCM:MeOH). All fractionscontaining clean product were combined and concentrated to give benzyl4-(2-(((S)-1-(tert-butoxycarbonyl)-2-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(264 mg, 0.361 mmol, 99.7% yield). ES+APCI MS m/z 732.4 [M+H]⁺.

Step B: benzyl2-(cyanomethyl)-4-(2-(((S)-2-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate.benzyl4-(2-(((S)-1-(tert-butoxycarbonyl)-2-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(264 mg, 0.361 mmol) was dissolved in dichloromethane (3607 μl, 0.361mmol) and treated with TFA (556 μl, 7.21 mmol). The reaction stirred atroom temperature for 1 hour. LC/MS showed reaction completion. Thereaction was concentrated in vacuo and treated with saturated bicarb.The aqueous layer was extracted with DCM (2×) and the combined organicsdried over Na2SO4 and concentrated in vacuo to give benzyl2-(cyanomethyl)-4-(2-(((S)-2-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(210 mg, 0.332 mmol, 92.2% yield). ES+APCI MS m/z 632.3 [M+H]⁺.

Step C: benzyl2-(cyanomethyl)-4-(2-(((S)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate.benzyl 2-(cyanomethyl)-4-(2-(((S)-2-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(105 mg, 0.1662 mmol) was dissolved in formic acid (94.05 μl, 2.493mmol) and treated with Formaldehyde (1868 μl, 24.93 mmol). The reactionmixture stirred at 85° C. for 1 hour. LC/MS showed reaction completion.The reaction was cooled to room temperature and treated with saturatedbicarb and the mixture was extracted with DCM (2×) and the organicscombined and dried over Na2SO4 The combined organics were concentratedin vacuo and chromatagraphed on the CombiFlash (0%-10% DCM:MeOH). Allfractions containing clean product were combined and concentrated invacuo to give benzyl2-(cyanomethyl)-4-(2-(((S)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(75 mg, 0.1161 mmol, 69.88% yield). ES+APCI MS m/z 646.4 [M+H]⁺.

Step D:2-(4-(2-(((S)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.A solution of benzyl2-(cyanomethyl)-4-(2-(((S)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(117 mg, 0.181 mmol) in EtOH (1812 μl, 0.181 mmol) and THF (1812 μl,0.181 mmol) was purged with N₂ for 5 minutes. To this solution was addedPalladium (96.4 mg, 0.0453 mmol) (Degussa Type, 10 wt %, 50% H₂O), andwas immediately capped and purged with N₂ for an additional 5 min. Thesolution was then stirred under H₂ atmosphere for 1 hour. LC/MS showedclean desired product. The mixture was diluted with MeOH and filteredthrough packed celite. The filtrate was then concentrated in vacuo toprovide2-(4-(2-(((S)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(88 mg, 0.172 mmol, 94.9% yield). ES+APCI MS m/z 512.3 [M+H]⁺.

Step E:2-(1-acryloyl-4-(2-(((S)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.To a suspension of2-(4-(2-(((S)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(88 mg, 0.17 mmol) in dichloromethane (1720 μl, 0.17 mmol) at ambienttemperature was added Acyloyl Chloride (14 μl, 0.17 mmol) followed byHunig's base (60 μl, 0.34 mmol). The reaction was then stirred atambient temperature for 30 minutes. LC/MS showed reaction completion.The reaction mixture was concentrated in vacuo. The concentrate wasresuspended in a 60:40 mixture of ACN:H2O and purified on the Gilson(prep HPLC) using 5->95% ACN/0.1% TFA in water/0.1% TFA as eluent.Fractions containing product were combined and free based with saturatedbicarb and the organics extracted with DCM. The organics were dried overMgSO4 and concentrated in vacuo to give2-(1-acryloyl-4-(2-(((S)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(14 mg, 0.025 mmol, 14% yield). ES+APCI MS m/z 566.3 [M+H]⁺.

Example 252 tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

Step A: (S2)-pyrrolidin-2-ylmethanol: To a solution of (S)-tert-butyl2-(hydroxymethyl)pyrrolidine-1-carboxylate (2 g, 9.94 mmol) in CH₂Cl₂(40 mL) was added HCl (4 M in dioxane, 49.69 mL) at 0° C. under anitrogen atmosphere. After stirring at 15° C. for 30 min, the mixturewas concentrated under vacuum. (S)-pyrrolidin-2-ylmethanol (1.37 g, 9.96mmol, 100% yield, HCl) was obtained as a yellow solid.

Step B: [(2S)-1-isopropylpyrrolidin-2-yl] methanol: A mixture of[(2S)-pyrrolidin-2-yl]methanol (750 mg, 7.41 mmol, 724 uL) and acetone(4.31 g, 74.2 mmol, 5.46 mL) in MeOH (20 mL) was hydrogenated under H₂(30 psi) with Pd/C (100 mg, 7.41 mmol, 10% purity) at 15° C. for 3hours. The mixture was filtered and concentrated under vacuum.[(2S)-1-isopropylpyrrolidin-2-yl]methanol (0.821 g, 5.73 mmol, 77.3%yield) was obtained as a yellow oil. ¹H NMR (400 MHz, methanol-d₄)δ=3.54 (dd, J=4.0, 10.8 Hz, 1H), 3.40-3.35 (m, 1H), 2.99-2.86 (m, 3H),2.60-2.50 (m, 1H), 1.94-1.82 (m, 1H), 1.82-1.66 (m, 3H), 1.15 (d, J=6.4Hz, 3H), 1.08 (d, J=6.4 Hz, 3H).

Step C: tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate: To a mixture of tert-butyl2-(cyanomethyl)-4-[2-methylsulfinyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(300 mg, 549 umol) and [(2S)-1-isopropylpyrrolidin-2-yl]methanol (157mg, 1.10 mmol) in THF (5 mL) was added t-BuONa (158 mg, 1.65 mmol).After stirring at 20° C. for 0.5 hour, the reaction mixture wasneutralized with HCl (1 M) to pH=7 while holding the solutiontemperature to 0° C., and then the mixture was concentrated underreduced pressure. The residue was purified by reversed phase flash[water (0.1% TFA)/acetonitrile]. The desired fractions were collectedand neutralized with saturated NaHCO₃ solution and extracted with ethylacetate (200 mL). The organic layer was dried over sodium sulfate,filtered and concentrated under vacuum. tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(174 mg, 278 umol, 50.7% yield, 100% purity) was obtained as a yellowoil. ESI MS m/z 626.2 [M+H]⁺.

Step D:2-[4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile:To a solution of tert-butyl 2-(cyanomethyl)-4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(174 mg, 278 umol) in CH₂Cl₂ (5 mL) was added TFA (7.70 g, 67.5 mmol,5.00 mL) at 0° C. under nitrogen atmosphere. After stirring at 15° C.for 0.5 h, the mixture was concentrated under vacuum.2-[4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(178 mg, crude, TFA) was obtained as a yellow oil. ESI MS m/z 526.1[M+H]⁺.

Step E:2-[4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile:To a mixture of2-[4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(178 mg, crude, TFA salt) and DIEA (360 mg, 2.78 mmol, 485 uL) in CH₂Cl₂(5 mL) was added prop-2-enoyl prop-2-enoate (28.1 mg, 223 umol) at 0° C.The mixture was stirred at 20° C. for 1 hour. The reaction mixture wasquenched with NaHCO₃ saturated solution (5 mL) at 0° C., and thenextracted with CH₂Cl₂ (2×25 mL). The combined organic layers were washedwith brine (1×50 mL), dried over sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by prep-HPLC(column: Boston Green ODS 150*30 5 u; mobile phase: [water (0.225%FA)-ACN]; B %: 27%-54%, 10 min),2-[4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(11.7 mg, 18.3 umol, two steps 6.58% yield, 97.9% purity, FA) wasobtained as a brown solid. ESI MS m/z 580.2 [M+H]⁺.

Example 2532-(1-acryloyl-4-(7-(7-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: (7-chloro-3,4-dihydronaphthalen-1-yl) trifluoromethanesulfonate:To a mixture of 7-chlorotetralin-1-one (2 g, 11.1 mmol, 1 eq) and DIEA(4.29 g, 33.2 mmol, 5.79 mL) in DCM (35 mL) was added Tf₂O (4.69 g, 16.6mmol, 2.74 mL) in one portion at 0° C. under N₂. The mixture was stirredat 25° C. for 5 hours. The reaction mixture was concentrated underreduced pressure. The residue was purified by column chromatography(SiO₂, Petroleum ether/Ethyl acetate=200/1 to 50/1).(7-chloro-3,4-dihydronaphthalen-1-yl) trifluoromethanesulfonate (2.25 g,7.02 mmol, 63.4% yield, 97.6% purity) was obtained as a colorless oil.¹H NMR (400 MHz, chloroform-d) δ 7.32 (d, J=2.0 Hz, 1H), 7.24 (dd,J=2.0, 8.0 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 6.10 (t, J=4.8 Hz, 1H),2.88-2.80 (m, 2H), 2.53 (dt, J=4.8, 8.0 Hz, 2H).

Step B: (7-chloro-1-naphthyl) trifluoromethanesulfonate: To a mixture of(7-chloro-3,4-dihydronaphthalen-1-yl) trifluoromethanesulfonate (1.57 g,5.02 mmol) in dioxane (35 mL) was added DDQ (2.28 g, 10.0 mmol) in oneportion under N₂. The mixture was stirred at 25° C. for 30 min, thenheated to 105° C. and stirred for 5 hours. The reaction mixture wasconcentrated under reduced pressure to remove 1,4-dioxane. The residuewas purified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=200/1 to 50/1). (7-chloro-1-naphthyl) trifluoromethanesulfonate(1.24 g, 3.94 mmol, 78.5% a yield, 98.7% purity) was obtained as acolorless oil. ¹H NMR (400 MHz, chloroform-d) δ=8.05 (d, J=2.0 Hz, 1H),7.87-7.83 (m, 2H), 7.57-7.47 (m, 3H).

Title compound was prepared as in Example 210 Steps E-G, substituting(7-chloro-1-naphthyl) trifluoromethanesulfonate for1-bromo-2-(trifluoromethyl)benzene in step E and also substitutingprop-2-enoyl prop-2-enoate for acryloyl chloride in step G. ESI MS m/z586.1 [M+H]⁺.

Example 2542-[4-[7-(5-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Title compound was prepared as in Example 210 Steps E-G, substituting1-bromo-5-fluoronaphthalene for 1-bromo-2-(trifluoromethyl)benzene instep E and also substituting prop-2-enoyl prop-2-enoate for acryloylchloride in step G. ESI MS m/z 570.3 [M+H]⁺.

Example 2552-[4-[7-(7-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-pro-2-enoyl-piperazin-2-yl]acetonitrile

Step A: (7-methoxy-3,4-dihydronaphthalen-1-yl)trifluoromethanesulfonate: To the solution of 7-methoxytetralin-1-one (1g, 5.67 mmol) and DIEA (2.20 g, 17.0 mmol, 2.97 mL) in DCM (15 mL) wasadded Tf₂O (2.40 g, 8.51 mmol, 1.40 mL) dropwise, then the mixture wasstirred at 20° C. for 12 hours. The reaction mixture was concentratedunder vacuum. The residue was purified by silica gel chromatography(PE:EtOAc from 1:0 to 100:1) to give(7-methoxy-3,4-dihydronaphthalen-1-yl) trifluoromethanesulfonate (1.7 g,5.24 mmol, 92.3% yield, 95.0% purity) as yellow oil. ¹H NMR (400 MHz,chloroform-d) δ=7.06 (d, J=8.4 Hz, 1H), 6.75 (dd, J=2.4, 8.4 Hz, 1H),6.66 (d, J=2.4 Hz, 1H), 6.45 (s, 1H), 3.80 (s, 3H), 3.04-2.96 (m, 2H),2.68 (t, J=8.4 Hz, 2H).

Step 2: (7-methoxy-1-naphthyl) trifluoromethanesulfonate: A mixture of(7-methoxy-3,4-dihydronaphthalen-1-yl) trifluoromethanesulfonate (1.7 g,5.51 mmol) and DDQ (2.50 g, 11.0 mmol) in dioxane (30 mL) was stirred at105° C. for 12 hours. The reaction mixture was concentrated undervacuum. The residue was purified by silica gel chromatography (PE:EtOAcfrom 1:0 to 50:1) to give (7-methoxy-1-naphthyl)trifluoromethanesulfonate (1.41 g, 4.14 mmol, 75.1% yield, 90.0% purity)as a colourless oil. ¹H NMR (400 MHz, chloroform-d) δ=7.84 (d, J=9.2 Hz,1H), 7.78 (d, J=8.8 Hz, 1H), 7.65 (d, J=2.4 Hz, 1H), 7.24-7.21 (m, 2H),7.15 (d, J=2.4 Hz, 1H), 3.94 (s, 3H).

Title compound was prepared as in Example 210 Steps E-G, substituting(7-methoxy-1-naphthyl) trifluoromethanesulfonate for1-bromo-2-(trifluoromethyl)benzene in step E and also substitutingprop-2-enoyl prop-2-enoate for acryloyl chloride in step G. ESI MS m/z582.4 [M+H]⁺.

Example 2561-(2-(methoxymethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: benzyl4-(4-(tert-butoxycarbonyl)-3-(methoxymethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:A solution of tert-butyl 2-(methoxymethyl)piperazine-1-carboxylate(0.715 g, 3.10 mmol) in N,N-dimethylacetamide (3 ml) was cooled on anice bath with stirring and solid benzyl2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (1.00g, 2.96 mmol) was added in small portions, followed by DIPEA (0.57 mL,3.25 mmol, 1.1 eq.). The resulting solution was allowed to warm up tor.t. over 1 hour, and then divided between water (15 mL) and MTBE (50mL). The organic layer was washed with water (2×10 mL), brine (10 mL),dried over Na₂SO₄ and evaporated in vacuo to give a yellow solid (1.54g, 98%). ES+APCI MS m/z 532.3, [M+H]⁺.

Step B: benzyl4-(4-(tert-butoxycarbonyl)-3-(methoxymethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:A mixture of crude benzyl4-(4-(tert-butoxycarbonyl)-3-(methoxymethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(500 mg, 0.940 mmol), (S)-(1-methylpyrrolidin-2-yl)methanol (216 mg,1.88 mmol), Cs₂CO₃ (612 mg, 1.88 mmol) and dioxane (0.5 mL) was flushedwith nitrogen. The vial was capped and stirred at 120° C. overnight. Thereaction mixture was cooled, divided between EtOAc (20 mL) and water (10mL), the organic layer was washed with water and brine (5 mL each),dried over Na₂SO₄ and evaporated in vacuo. The compound was purified bysilica gel chromatography, Redisep 40 g, eluting with 4 to 10%MeOH/DCM+0.2% NH₄OH to give a yellow solid (197 mg, 34%). ES+APCI MS m/z611.4 [M+H]⁺.

Step C: tert-butyl2-(methoxymethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:A mixture of benzyl4-(4-(tert-butoxycarbonyl)-3-(methoxymethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(197 mg, 0.323 mmol), methanol (10 mL) and palladium on carbon (10 mg,5%, Degussa type E101 NO/W) was degassed and stirred under hydrogenatmosphere (balloon) for 1 hour. The reaction mixture was filteredthrough Celite (2 mL), washed with MeOH (3×3 mL), evaporated in vacuo,and dried by evaporation with toluene in vacuo and under high vacuum togive a colorless solid (150 mg, 98%). ES+APCI MS m/z 477.2 [M+H]⁺.

Step D: tert-butyl2-(methoxymethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:A mixture of tert-butyl2-(methoxymethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido-[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(150 mg, 0.315 mmol), Cs₂CO₃ (308 mg, 0.944 mmol), dioxane (1 mL),1-iodonaphthalene (0.0689 ml, 0.472 mmol) andmethanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl)palladium(II)(26.3 mg, 0.0315 mmol) (RuPhos-Pd-G3) was purged with nitrogen, theflask was capped and stirred at 70° C. overnight. The reaction mixturewas cooled, divided between EtOAc (15 mL) and water (5 mL), the organiclayer was washed with water and brine (5 mL each), dried over Na₂SO₄ andevaporated in vacuo. The compound was purified by silica gelchromatography, Redisep 40 g, using 4 to 10% MeOH+0.5% NH₄HO as eluentto give a colorless solid, 131 mg, ES+APCI MS m/z 603.3 (M+H H⁺.

Step E:1-(2-methoxymethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one.Tert-butyl2-(methoxymethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(130 mg, 0.2157 mmol) was dissolved in 1M trifluoroacetic acid in DCM,and the resulted solution was allowed to stay at r.t. for 1 h. Thereaction mixture was divided between 2M Na₂CO₃ (5 mL) and DCM (15 mL),and the organic layer was evaporated in vacuo. The solid residue wasdissolved in DCM (5 mL), cooled on ice-EtOH-CO₂ bath with stirring to−30° C. and triethylamine (0.09 ml, 0.64 mmol) was added, followed byacryloyl chloride (0.035 ml, 0.43 mmol). After 1 min at −30° C. thereaction mixture was quenched with NH₄OH (0.05 mL) and evaporated invacuo and dried under high vacuum. The residue was dissolved in DCM (5mL), filtered through a cotton plug and purified by silica gelchromatography, Redisep 40 g, eluting with 5 to 10% MeOH/DCM+0.25% NH₄OHto give a colorless solid (19.6 mg, 16%). ES+APCI MS m/z 557.3, [M+H]⁺.

Example 2572-(1-acryloyl-4-(2-(((S)-1-(cyclopropylmethyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: benzyl2-(cyanomethyl)-4-(2-(((S)-1-(cyclopropylmethyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:In a conical bottom vial, a solution of benzyl4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(200 mg, 0.362 mmol) in dioxane (3616 μl, 0.362 mmol) was sparged withArgon for 5 minutes. (S)-(1-(cyclopropylmethyl)pyrrolidin-2-yl)methanol(168 mg, 1.08 mmol), Cs2CO3 (353 mg, 1.08 mmol), Rhuphos Pd G3 (30.2 mg,0.0362 mmol) were sequentially added under Argon and sparged for anadditional 5 minutes. The reaction mixture was capped and heated at 100°C. for 1 hour. LC/MS showed reaction completion. EtOAc was added andwashed with brine (2×). The combined organics were dried over Na2SO4 andconcentrated in vacuo. The concentrate was purified by flashchromatography eluting with 0-20% DCM/MeOH+2% NH4OH. All fractionscontaining clean desired product were combined and concentrated to givebenzyl2-(cyanomethyl)-4-(2-(((S)-1-(cyclopropylmethyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(90 mg, 0.134 mmol, 37.0% yield). ES+APCI MS m/z 672.4 [M+H]⁺.

Step B:2-(4-(2-(((S)-1-(cyclopropylmethyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:A solution of benzyl2-(cyanomethyl)-4-(2-(((S)-1-(cyclopropylmethyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(90 mg, 0.13 mmol) in EtOH (1340 μl, 0.13 mmol) and THF (1340 μl, 0.13mmol) was purged with N₂ for 5 min. To this solution was added Palladium(36 mg, 0.033 mmol)(Degussa Type, 10 wt %, 50% H2O), and was immediatelycapped and purged with N₂ for an additional 5 min. The solution was thenstirred under H₂ introduced via vacuum followed by balloon pressure. Themixture was then stirred at ambient temperature for 1 hour. LC/MS showeddesired product. The mixture was diluted with MeOH and filtered throughpacked celite. The filtrate was then concentrated in vacuo to provide2-(4-(2-(((S)-1-(cyclopropylmethyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(71 mg, 0.13 mmol, 99% yield). ES+APCI MS m/z 538.3 [M+H]⁺.

Step C:2-(1-acryloyl-4-(2-(((S)-1-(cyclopropylmethyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:To a suspension of2-(4-(2-(((S)-1-(cyclopropylmethyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(71 mg, 0.132 mmol) in dichloromethane (1320 μl, 0.132 mmol) at ambienttemperature was added Acryloyl Chloride (10.7 μl, 0.132 mmol) followedby Hunig's base (46.1 μl, 0.264 mmol). The reaction was then stirred atambient temperature for 1 hour. LC/MS showed reaction completion. Thereaction mixture was concentrated in vacuo. The concentrate wasresuspended in a 60:40 mixture of ACN:H2O and purified on the Gilson(prep HPLC) eluting with 5->95% ACN/0.1% TFA in water/0.1% TFA:Fractions containing product were combined and free based with saturatedbicarb and the organics extracted with DCM. The organics were dried overMgSO₄ and concentrated in vacuo to give2-(1-acryloyl-4-(2-(((S)-1-(cyclopropylmethyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(15.7 mg, 0.0265 mmol, 20.1% yield). ES+APCI MS m/z 592.4 [M+H]⁺.

Example 2582-[4-[7-(1-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Title compound was prepared as in Example 210 Steps E-G, substituting1-bromoisoquinoline for 1-bromo-2-(trifluoromethyl)benzene in step E andalso substituting prop-2-enoyl prop-2-enoate for acryloyl chloride instep G. ESI MS m/z 553.3 [M+H]⁺.

Example 2592-[4-[7-(6-fluoro-1-naphthyl)-2-[[(2%)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: (6-fluoro-1-naphthyl) trifluoromethanesulfonate: To a solutionof 6-fluoronaphthalen-1-ol (0.10 g, 617 umol) and DIEA (159 mg, 1.23mmol, 215 uL) in dichloromethane (3 mL) was addedtrifluoromethylsulfonyl trifluoromethanesulfonate (191 mg, 678 umol, 112uL,) at 0° C. After stirred at 0° C. for 1 hour, the mixture was dilutedwith water (5 mL) and extracted with dichloromethane (3×5 mL). Theorganic layers were washed with brine (1×5 mL), dried over Na₂SO₄,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography (SiO₂, petroleum ether/ethyl acetate=3/1) to give(6-fluoro-1-naphthyl) trifluoromethanesulfonate (0.17 g, 543 umol, 88.1%yield) as a colourless oil. ¹H NMR (400 MHz, chloroform-d) δ=8.10 (dd,J=5.2, 8.8 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.58-7.50 (m, 2H), 7.48-7.40(m, 2H).

Title compound was prepared as in Example 210 Steps E-G, substituting1(6-fluoro-1-naphthyl) trifluoromethanesulfonate for1-bromo-2-(trifluoromethyl)benzene in step E and also substitutingprop-2-enoyl prop-2-enoate for acryloyl chloride in step G ESI MS m/z570.3 [M+H]⁺.

Example 2602-[4-[7-(4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Title compound was prepared as in Example 210 Steps E-G, substituting4-bromoisoquinoline for 1-bromo-2-(trifluoromethyl)benzene in step E andalso substituting prop-2-enoyl prop-2-enoate for acryloyl chloride instep G. ESI MS m/z 553.1 [M+H]⁺.

Example 2612-[1-(2-methylprop-2-enoyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

Title compound was prepared as in Example 210 Steps E-G, substituting1-bromonaphthalene for 1-bromo-2-(trifluoromethyl)benzene in step E andalso substituting 2-methylprop-2-enoyl chloride for acryloyl chloride instep G ESI MS m/z 566.4 [M+H]⁺.

Example 2622-[4-[7-(5-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Title compound was prepared as in Example 210 Steps E-G, substituting5-bromoisoquinoline for 1-bromo-2-(trifluoromethyl)benzene in step E andalso substituting prop-2-enoyl prop-2-enoate for acryloyl chloride instep G. ESI MS m/z 553.4 [M+H]⁺.

Example 2632-[1-[(E)-but-2-enoyl]-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

Title compound was prepared as in Example 210 Steps E-G, substituting1-bromonaphthalene for 1-bromo-2-(trifluoromethyl)benzene in step E and(E)-but-2-enoyl chloride for acryloyl chloride in step G. ESI MS m/z566.4 [M+H]⁺.

Example 2642-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(5-quinolyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Title compound was prepared as in Example 210 Steps E-G, substituting5-bromoquinoline for 1-bromo-2-(trifluoromethyl)benzene in step E andalso substituting prop-2-enoyl prop-2-enoate for acryloyl chloride instep G. ESI MS m/z 553.4 [M+H]⁺.

Example 2652-(1-acryloyl-4-(7-(3-methyl-2-(trifluoromethyl)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was synthesized according to Example 210, Steps E-G using1-bromo-3-methyl-2-(trifluoromethyl)benzene for 1-bromonaphthalene inStep E. ES+APCI MS m/z 584.3 [M+H]⁺.

Example 2662-(1-acryloyl-4-(2-(((S)-1-(2-methoxyethyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was synthesized according to Example 147, Steps F-J,using (S)-(1-(2-methoxyethyl)pyrrolidin-2-yl)methanol in place of(S)-(1-methylpyrrolidin-2-yl)methanol in Step F. ES+APCI MS m/z 596.3[M+H]⁺.

Example 2672-((S)-1-acryloyl-4-(2-(((R)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was synthesized according to Example 234 using(R)-(1-methylpyrrolidin-2-yl)methanol in place of(S)-(1-methylpyrrolidin-2-yl)methanol in Step F. ES+APCI MS m/z 552.3[M+H]⁺.

Example 2682-(1-acryloyl-4-(2-(((2S,4R)-4-methoxy-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was synthesized according to Example 220, (Steps C-G),using tert-butyl(2S,4R)-2-(hydroxymethyl)-4-methoxypyrrolidine-1-carboxylate in place of(2S,4R)-1-(tert-Butoxycarbonyl)-4-fluoro-2-hydroxymethylpyrrolidine inStep C. ES+APCI MS m/z 582.3 [M+H]⁺.

Example 2692-(1-acryloyl-4-(2-(2-(dimethylamino)-2-methylpropoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

The title compound was synthesized following Example 147 substituting2-Dimethylamino-2-methyl-1-propanol for(S)-(1-(cyclopropylmethyl)pyrrolidin-2-yl)methanol in Step F. ES+APCI MSm/z 554.4 [M+H]⁺.

Example 2702-(1-acryloyl-4-(2-(((R)-4-methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was synthesized according to Example 147, Steps F-J,using (R)—N-Boc-2-hydroxymethylmorpholine in place of(S)-(1-methylpyrrolidin-2-yl)methanol in Step F. ES+APCI MS m/z 568.3[M+H]⁺.

Example 2712-(1-acryloyl-4-(2-(((S)-4-methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was synthesized according to Example 147, Steps F-J,using (S)—N-Boc-2-hydroxymethylmorpholine in place of(S)-(1-methylpyrrolidin-2-yl)methanol in Step F. ES+APCI MS m/z 568.3[M+H]⁺.

Example 2722-(1-acryloyl-4-(2-(((S)-4-methylmorpholin-3-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was synthesized according to Example 147, Steps F-J,using tert-butyl (R)-3-(hydroxymethyl)morpholine-4-carboxylate in placeof (S)-(1-methylpyrrolidin-2-yl)methanol in Step F. ES+APCI MS m/z 568.3[M+H]⁺.

Example 2732-(1-acryloyl-4-(2-(((R)-4-methylmorpholin-3-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was synthesized according to Example 147, Steps F-J,using tert-butyl (S)-3-(hydroxymethyl)morpholine-4-carboxylate in placeof (S)-(1-methylpyrrolidin-2-yl)methanol in Step F. ES+APCI MS m/z 568.3[M+H]⁺.

Example 2742-((S)-1-acryloyl-4-(7-(3-fluoro-2-(trifluoromethyl)phenyl)-2-(((R)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was synthesized according to Example 234, Steps G-J using(R)-(1-methylpyrrolidin-2-yl)methanol in place of(S)-(1-methylpyrrolidin-2-yl)methanol in Step F and1-bromo-3-fluoro-2-(trifluoromethyl)benzene for 1-bromonaphthalene inStep H ES+APCI MS m/z 588.3 [M+H]⁺.

Example 2752-(1-acryloyl-4-(7-(2-fluoro-6-(trifluoromethyl)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was synthesized according to Example 210, Steps E-G using2-bromo-1-fluoro-3-(trifluoromethyl)benzene for 1-bromonaphthalene inStep E. ES+APCI MS m/z 588.3 [M+H]⁺.

Example 2762-(1-acryloyl-4-(7-(4-fluoro-2-(trifluoromethyl)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was synthesized according to Example 210, Steps E-G using1-bromo-4-fluoro-2-(trifluoromethyl)benzene for 1-bromonaphthalene inStep E. ES+APCI MS m/z 588.3 [M+H]⁺.

Example 2772-(1-acryloyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was synthesized according to Example 210, Steps E-G using1-bromo-3-chloro-2-(trifluoromethyl)benzene for 1-bromonaphthalene inStep E and THF in place EtOH/THF in Step F. ES+APCI MS m/z 604.3 [M+H]⁺.

Example 2782-(1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(quinolin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was prepared as in Example 210 Steps E-G, substituting4-bromoquinoline for 1-bromo-2-(trifluoromethyl)benzene in step E andalso substituting prop-2-enoyl prop-2-enoate for acryloyl chloride instep G.

Example 279 2-(1-acryloyl-4-(2-(2-(dimethylamino)ethoxy)-7-(2-(tifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was prepared as in Example 210, substituting N,N-dimethyl-ethanolamine for (2S)-1-Ethyl-2-pyrrolidinyl]methanol in stepC and also substituting prop-2-enoyl prop-2-enoate for acryloyl chloridein step G.

Example 2802-(4-(2-(3-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(2-(trifluoromethylphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-acryloylpiperazin-2-yl)acetonitrile

Title compound was prepared as in Example 210, substituting3-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propan-1-ol for(2S)-1-Ethyl-2-pyrrolidinyl]methanol in step C and also substitutingprop-2-enoyl prop-2-enoate for acryloyl chloride in step G.

Example 2812-(1-acryloyl-4-(2-(((R)-1-methylpyrrolidin-3-yl)methoxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was prepared as in Example 210, substituting(R)-(1-methylpyrrolidin-3-yl)methanol for(2S)-1-Ethyl-2-pyrrolidinyl]methanol in step C and also substitutingprop-2-enoyl prop-2-enoate for acryloyl chloride in step G.

Example 2822-(1-(3-methylbut-2-enoyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was prepared as in Example 210, substituting1-bromonaphthalene for 1-bromo-2-(trifluoromethyl)benzene in step E and3-methylbut-2-enoyl chloride for acryloyl chloride in step G.

Example 2832-(1-acryloyl-4-(2-(((R)-1-methylpyrrolidin-2-yl)methoxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was prepared as in Example 210, substituting(2R)-1-Ethyl-2-pyrrolidinyl]methanol for(2S)-1-Ethyl-2-pyrrolidinyl]methanol in step C and also substitutingprop-2-enoyl prop-2-enoate for acryloyl chloride in step G.

Example 2842-(1-acryloyl-4-(2-(2-(diethylamino)ethoxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was prepared as in Example 210, substituting N,N-diethyl-ethanolamine for (2S)-1-Ethyl-2-pyrrolidinyl]methanol in stepC and also substituting prop-2-enoyl prop-2-enoate for acryloyl chloridein step G.

Example 285

tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

Step 1: (S)-pyrrolidin-2-ylmethanol. To a solution of (S)-tert-butyl2-(hydroxymethyl) pyrrolidine-1-carboxylate (2 g, 9.94 mmol, 1 eq) inCH₂Cl₂ (40 mL) was added HCl (4 M in dioxane, 49.69 mL, 20 eq) at 0° C.under nitrogen atmosphere. After stirred at 15° C. for 30 min, themixture was concentrated under vacuum. Compound(S)-pyrrolidin-2-ylmethanol (1.37 g, 9.96 mmol, 100% yield, HC) wasobtained as a yellow solid.

Step 2: [(2S)-1-isopropylpyrrolidin-2-yl]methanol. A mixture of[(2S)-pyrrolidin-2-yl]methanol (750 mg, 7.41 mmol, 724 uL, 1 eq) andacetone (4.31 g, 74.2 mmol, 5.46 mL, 10 eq) in MeOH (20 mL) washydrogenated under H₂ (30 psi) with Pd/C (100 mg, 7.41 mmol, 10% purity,1 eq) as a catalyst at 15° C. for 3 hours. The mixture was filtered andconcentrated under vacuum. Compound[(2S)-1-isopropylpyrrolidin-2-yl]methanol (0.821 g, 5.73 mmol, 77.3%yield) was obtained as a yellow oil.

¹H NMR (400 MHz, methanol-d₄) δ=3.54 (dd, J=4.0, 10.8 Hz, 1H), 3.40-3.35(m, 1H), 2.99-2.86 (m, 3H), 2.60-2.50 (m, 1H), 1.94-1.82 (m, 1H),1.82-1.66 (m, 3H), 1.15 (d, J=6.4 Hz, 3H), 1.08 (d, J=6.4 Hz, 3H).

Step A: tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4d]pyrimidin-4-yl]piperazine-1-carboxylate.To a mixture of tert-butyl2-(cyanomethyl)-4-[2-methylsulfinyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(300 mg, 549 umol, 1 eq) and [(2S)-1-isopropylpyrrolidin-2-yl]methanol(157 mg, 1.10 mmol, 2 eq) in THF (5 mL) was added t-BuONa (158 mg, 1.65mmol, 3 eq). After stirred at 20° C. for 0.5 hour, the reaction mixturewas neutralized with HCl (1 mol/L) to pH=7 at 0° C., and then themixture was concentrated under reduced pressure. The residue waspurified by reversed phase flash [water (0.1% TFA)/acetonitrile]. Thedesired fractions were collected and neutralized with saturated NaHCO₃solution and extracted with ethyl acetate (200 mL). The organic layerwas dried over sodium sulfate, filtered and concentrated under vacuum.Compound tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(174 mg, 278 umol, 50.7% yield, 100% purity) was obtained as a yellowoil. LCMS [ESI, M+1]: 626.

Step B:2-[4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl 2-(cyanomethyl)-4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(174 mg, 278 umol, 1 eq) in CH₂Cl₂ (5 mL) was added TFA (7.70 g, 67.5mmol, 5.00 mL, 243 eq) at 0° C. under nitrogen atmosphere. After stirredat 15° C. for 0.5 h, the mixture was concentrated under vacuum. Compound2-[4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-S1-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(178 mg, crude, TFA) was obtained as a yellow oil. LCMS [ESI, M+1]: 526.

Step C:2-[4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a mixture of2-[4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(178 mg, crude, TFA) and DIEA (360 mg, 2.78 mmol, 485 uL) in CH₂Cl₂ (5mL) was added prop-2-enoyl prop-2-enoate (28.1 mg, 223 umol) at 0° C.The mixture was stirred at 20° C. for 1 hour. The reaction mixture wasquenched with NaHCO₃ saturated solution (5 mL) at 0° C., and thenextracted with CH₂Cl₂ (2×25 mL). The combined organic layers were washedwith brine (1×50 mL), dried over sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by prep-HPLC(column: Boston Green ODS 150*30 5 u; mobile phase: [water (0.225%FA)-ACN]; B %: 27%-54%, 10 min) Title compound2-[4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(11.7 mg, 18.3 umol, two steps 6.58% yield, 97.9% purity, FA) wasobtained as a brown solid. LCMS [ESI, M+1]: 580.

¹H NMR (400 MHz, Acetic acid-d4) δ=8.28-8.19 (m, 1H), 8.08 (s, 1H),7.91-7.83 (m, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.56-7.47 (m, 2H), 7.44 (t,J=7.6 Hz, 1H), 7.20 (d, J=7.2 Hz, 1H), 6.94-6.71 (m, 1H), 6.38 (br d,J=16.8 Hz, 1H), 5.87 (br d, J=10.4 Hz, 1H), 5.15 (br s, 1H), 4.92-4.54(m, 4H), 4.42 (br d, J=12.0 Hz, 1H), 4.34 (br s, 2H), 4.13 (br s, 2H),3.95 (br s, 1H), 3.85-3.21 (m, 7H), 3.20-2.84 (m, 3H), 2.42-2.25 (m,1H), 2.24-2.07 (m, 3H), 1.43 (d, J=6.4 Hz, 3H), 1.39 (d, J=6.4 Hz, 3H).

Example 286

2-(1-acryloyl-4-(7-(7-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

(Step 1: (7-chloro-3,4-dihydronaphthalen-1-yl)trifluoromethanesulfonate. To a mixture of 7-chlorotetralin-1-one (2 g,11.1 mmol, 1 eq) and DIEA (4.29 g, 33.2 mmol 5.79 mL, 3 eq) in DCM (35mL) was added Tf₂O (4.69 g, 16.6 mmol, 2.74 mL, 1.5 eq) in one portionat 0° C. under N₂. The mixture was stirred at 25° C. for 5 hours. Thereaction mixture was concentrated under reduced pressure. The residuewas purified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=200/1 to 50/1). Compound (7-chloro-3,4-dihydronaphthalen-1-yl)trifluoromethanesulfonate (2.25 g, 7.02 mmol, 63.4% yield, 97.6% purity)was obtained as a colorless oil.

¹H NMR (400 MHz, chloroform-d) δ=7.32 (d, J=2.0 Hz, 1H), 7.24 (dd,J=2.0, 8.0 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 6.10 (t, J=4.8 Hz, 1H),2.88-2.80 (m, 2H), 2.53 (dt, J=4.8, 8.0 Hz, 2H).

Step 2: (7-chloro-1-naphthyl) trifluoromethanesulfonate. To a mixture of(7-chloro-3,4-dihydronaphthalen-1-yl) trifluoromethanesulfonate (1.57 g,5.02 mmol, 1 eq) in dioxane (35 mL) was added DDQ (2.28 g, 10.0 mmol, 2eq) in one portion under N₂. The mixture was stirred at 25° C. for 30min, then heated to 105° C. and stirred for 5 hours. The reactionmixture was concentrated under reduced pressure to remove 1,4-dioxane.The residue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=200/1 to 50/1). Compound (7-chloro-1-naphthyl)trifluoromethanesulfonate (1.24 g, 3.94 mmol, 78.5% yield, 98.7% purity)was obtained as a colorless oil.

¹H NMR (400 MHz, chloroform-d) δ=8.05 (d, J=2.0 Hz, 1H), 7.87-7.83 (m,2H), 7.57-7.47 (m, 3H).

Step A: tert-butyl4-[7-(7-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.To a mixture of tert-butyl2-(cyanomethyl)-4-[2-[(1-methylpyrrolidin-2-yl)methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 424 umol, 1 eq) and (7-chloro-1-naphthyl)trifluoromethanesulfonate (264 mg, 848 umol, 2 eq) in toluene (20 mL)was added Pd₂(dba)₃ (38.8 mg, 42.4 umol, 0.1 eq), RuPhos (39.6 mg, 84.8umol, 0.2 eq) and Cs₂CO₃ (414 mg, 1.27 mmol, 3 eq) under N₂. The mixturewas heated to 110° C. and stirred for 5 hours. The mixture was dilutedwith water (10.0 mL) and extracted with ethyl acetate (3×15.0 mL) Theextracts were washed with brine (1×20.0 mL), dried over Na₂SO₄, filteredand concentrated under vacuum. The residue was purified by reversedphase flash [water (0.1% TFA)/acetonitrile]. The desired fractions werecollected and neutralized with saturated NaHCO₃ solution and extractedwith ethyl acetate (1×30 mL). The organic layer was dried over sodiumsulfate, filtered and concentrated under vacuum. Compound tert-butyl4-[7-(7-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(200 mg, 316 umol, 74.6% yield, 100% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 632.

¹H NMR (400 MHz, chloroform-d) δ=8.20 (d, J=2.0 Hz, 1H), 7.80 (d, J=8.8Hz, 1H), 7.59 (d, J=8.2 Hz, 1H), 7.48-7.38 (m, 2H), 7.18 (d, J=7.2 Hz,1H), 4.63 (br s, 1H), 4.43 (br dd, J=4.8, 10.3 Hz, 1H), 4.29-4.16 (m,3H), 4.09-3.89 (m, 2H), 3.42 (br s, 1H), 3.35-3.20 (m, 3H), 3.17-2.65(m, 7H), 2.52 (s, 3H), 2.33 (br d, J=7.6 Hz, 1H), 2.14-2.06 (m, 1H),1.88-1.71 (m, 4H).

Step B:2-[4-[7-(7-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a mixture of tert-butyl4-[7-(7-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(200 mg, 316 umol, 1 eq) in DCM (2.5 mL) was added TFA (541 mg, 4.75mmol, 351 uL, 15 eq) in one portion at 0° C. under N₂. Then the mixturewas stirred at 25° C. for 2 hours. The reaction mixture was concentratedunder reduced pressure. Compound2-[4-[7-(7-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(204 mg, 316 umol, 99.8% yield, TFA) was obtained as a brown solid. LCMS[ESI, M+1]: 532.

Step C:2-[4-[7-(7-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a mixture of2-[4-[7-(7-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(204 mg, 316 umol, 1 eq, TFA) and TEA (160 mg, 1.58 mmol, 220 uL, 5 eq)in DCM (1.5 mL) was added prop-2-enoyl prop-2-enoate (39.8 mg, 316 umol,1 eq) in one portion at 0° C. After stirred at 25° C. for 1 h, thereaction mixture was quenched with saturated NaHCO₃ solution (1 mL) at0° C., then diluted with water (2 mL) and extracted with DCM (5 mL×3).The combined organic layers were washed with water (5 mL×1), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by prep-HPLC (column: Boston Green ODS 150×30 5 u; mobilephase: [water (0.225% FA)-ACN]; B %: 30%-54%, 10 min). Title compound2-[4-[7-(7-chloro-1-naphthyl)-2-[[(2N)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(36.0 mg, 56.1 umol, 17.8% yield, 98.7% purity, FA) was obtained as awhite solid. LCMS [ESI, M+1]: 586.

¹H NMR (400 MHz, chloroform-d) δ=8.42 (br s, 1H), 8.19 (d, J=1.6 Hz,1H), 7.80 (d, J=8.8 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.47-7.41 (m, 2H),7.19 (d, J=7.2 Hz, 1H), 6.61 (br s, 1H), 6.40 (br d, −16.8 Hz, 1H), 5.84(br d, J=10.8 Hz, 1H), 5.08 (br s, 1H), 4.91-4.75 (m, 2H), 4.48 (td,J=4.4, 12.0 Hz, 1H), 4.23 (br s, 3H), 4.07 (br d, J=11.2 Hz, 1H),3.82-3.58 (m, 2H), 3.56-3.08 (m, 6H), 3.08-2.92 (m, 2H), 2.89 (d, J=1.6Hz, 3H), 2.85-2.70 (m, 2H), 2.28 (qd, J=8.4, 12.5 Hz, 1H), 2.22-2.11),(m, 1H), 2.11-1.94 (m, 2H).

Example 287

2-[4-[7-(5-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: tert-butyl2-(cyanomethyl)-4-[7-(5-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of tert-butyl2-(cyanomethyl)-4-[2-[(1-methylpyrrolidin-2-yl)methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 424 umol, 1.30 eq) and 1-bromo-5-fluoro-naphthalene (73.4 mg,326 umol, 1.0 eq) in toluene (5.0 mL) was added Cs₂CO₃ (319 mg, 979umol, 3.0 eq), Pd₂(dba)₃ (29.9 mg, 32.6 umol, 0.10 eq) and RuPhos (22.8mg, 48.9 umol, 0.15 eq). The mixture was stirred at 110° C. for 12 hrs.The reaction mixture was concentrated under reduced pressure to removetoluene. The residue was diluted with H₂O (10.0 mL) and extracted withEthyl acetate (10.0 mL*3). The combined organic layers were washed withH₂O (10.0 mL), and concentrated under reduced pressure to give aresidue. The residue was purified by reversed phase flash [water (0.100%formic acid)/acetonitrile]. Compound tert-butyl2-(cyanomethyl)-4-[7-(5-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(140 mg, 211 umol, 64.5% yield) was obtained as a white solid. LCMS[ESI, M+1]: 616.

Step B:2-[4-[7-(5-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl2-(cyanomethyl)-4-[7-(5-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(130 mg, 211 umol, 1.0 eq) in DCM (2.0 mL) was added TFA (3.08 g, 27.0mmol, 2.00 mL, 128 eq). The mixture was stirred at 25° C. for 1 hr underN₂ atmosphere. The organic solvent was removed under vacuum. Compound2-[4-[7-(5-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(300 mg, crude) was obtained as a yellow oil. The crude product was useddirectly to the next step without further purification. LCMS [ESI, M+1]:517.

Step C:2-[4-[7-(5-fluoro-1-naphthyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrileTo a solution of2-[4-[7-(5-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(300 mg, TFA) in DCM (3.0 mL) was added Et₃N (200 mg, 1.98 mmol, 275 uL)and prop-2-enoyl prop-2-enoate (40.0 mg, 317 umol) at 0° C. The mixturewas stirred at 20° C. for 2 hrs. The reaction was washed with water(10.0 mL). The crude mixture was extracted with ethyl acetate (20.0mL*3). Combine extracts were washed with brine (50.0 mL), dried withNa₂SO₄ the solvent was then removed under vacuum. The residue waspurified by prep-HPLC (column-Boston Green ODS 150*30 5 u; mobile phase:[water (0.225% FA)-ACN]; B %: 26%-53%, 10 min) and lyophilization. Titlecompound2-[4-[7-(5-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enyl-piperazin-2-yl]acetonitrile(48.4 mg, 82.6 umol, two steps 40.0% yield, FA) was obtained as aoff-white solid. LCMS [ESI, M+1]: 570.

¹H NMR (400 MHz, CDCl₃) δ 8.41 (s, 1H), 7.91 (d, J=7.6 Hz, 1H), 7.80 (d,J=8.4 Hz, 1H), 7.42 (t, J=7.8 Hz, 1H), 7.38-7.32 (m, 1H), 7.13-7.07 (m,2H), 6.54-6.52 (m, 1H), 6.33 (m, 1H), 5.76 (d, J=10.4 Hz, 1H), 5.10-4.98(br, 4H), 4.74-4.69 (m, 1H), 4.41-4.36 (m, 1H), 4.16 (m, 3H), 3.99 (d,J=12.0 Hz, 1H), 3.61-3.60 (m, 1H), 3.14-3.29 (m, 4H), 3.11 (br, 2H),2.92-2.85 (m, 1H), 2.78 (s, 3H), 2.74-2.67 (m, 2H), 2.21-2.16 (m, 1H),2.09-2.04 (m, 1H), 1.98-1.91 (m, 2H).

Example 288

2-[4-[7-(7-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step 1: (7-methoxy-3,4-dihydronaphthalen-1-yl)trifluoromethanesulfonate. To the solution of 7-methoxytetralin-1-one (1g, 5.67 mmol, 1 eq), DIEA (2.20 g, 17.0 mmol, 2.97 mL, 3 eq) in DCM (15mL) was added Tf₂O (2.40 g, 8.51 mmol, 1.40 mL, 1.5 eq) dropwise, thenthe mixture was stirred at 20° C. for 12 hours. The reaction mixture wasconcentrated under vacuum. The residue was purified by silica gelchromatography (PE:EtOAc from 1:0 to 100:1) to give(7-methoxy-3,4-dihydronaphthalen-1-yl) trifluoromethanesulfonate (1.7 g,5.24 mmol, 92.3% yield, 95.0% purity) as yellow oil.

¹H NMR (400 MHz, chloroform-d) δ=7.06 (d, J=8.4 Hz, 1H), 6.75 (dd,J=2.4, 8.4 Hz, 1H), 6.66 (d, J=2.4 Hz, 1H), 6.45 (s, 1H), 3.80 (s, 3H),3.04-2.96 (m, 2H), 2.68 (t, J=8.4 Hz, 2H).

Step 2: (7-methoxy-1-naphthyl) trifluoromethanesulfonate. A mixture of(7-methoxy-3,4-dihydronaphthalen-1-yl) trifluoromethanesulfonate (1.7 g,5.51 mmol, 1 eq) and DDQ (2.50 g, 11.0 mmol, 2 eq) in dioxane (30 mL)was stirred at 105° C. for 12 hours. The reaction mixture wasconcentrated under vacuum. The residue was purified by silica gelchromatography (PE:EtOAc from 1:0 to 50:1) to give(7-methoxy-1-naphthyl) trifluoromethanesulfonate (1.41 g, 4.14 mmol,75.1% yield, 90.0% purity) as a colorless oil.

¹H NMR (400 MHz, chloroform-d) δ=7.84 (d, J=9.2 Hz, 1H), 7.78 (d, J=8.8Hz, 1H), 7.65 (d, J=2.4 Hz, 1H), 7.24-7.21 (m, 2H), 7.15 (d, J=2.4 Hz,1H), 3.94 (s, 3H).

Step A: tert-butyl2-(cyanomethyl)-4-[7-(7-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To the solution of tert-butyl2-(cyanomethyl)-4-[2-[(1-methylpyrrolidin-2-yl)methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(Intermediate 66, 200 mg, 424 umol, 1 eq), (7-methoxy-1-naphthyl)trifluoromethanesulfonate (260 mg, 848 umol, 2 eq), RuPhos (39.6 mg,84.8 umol, 0.2 eq), Cs₂CO₃ (414 mg, 1.27 mmol, 3 eq) in toluene (6 mL)was added Pd₂(dba)₃ (38.8 mg, 42.4 umol, 0.1 eq) under N₂. Thesuspension was degassed under vacuum and purged with N₂ several times.The mixture was stirred under N₂ at 90° C. for 12 hours. Water (5 mL)was added into the mixture. The resulting mixture was diluted with EtOAc(5 mL) and extracted with EtOAc (3×10 mL). The combined organic layerswere dried over anhydrous Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by reversed phase flash column(ACN/Water (0.1% FA)=34%) to give tert-butyl2-(cyanomethyl)-4-[7-(7-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(100 mg, 151 umol, 35.7% yield, 95.0% purity) as brown solid. LCMS [ESI,M+1]: 628.

¹H NMR (400 MHz, chloroform-d) δ 7.69 (d, J=9.2 Hz, 1H) 7.63 (d, J=8.8Hz, 1H), 7.17 (dd, J=2.4, 9.2 Hz, 1H), 7.09 (d, J=2.0 Hz, 1H), 7.03 (d,J=2.4 Hz, 1H), 6.96 (dd, J=2.4, 8.8 Hz, 1H), 4.61 (br s, 1H), 4.52-4.30(m, 3H), 4.20 (ddd, J=3.2, 6.8, 10.4 Hz, 1H), 4.02 (br d, J=13.6 Hz,2H), 3.92 (s, 3H), 3.87 (br d, J=13.2 Hz, 1H), 3.76-3.68 (m, 1H),3.55-3.43 (m, 1H), 3.25 (br dd, J=3.6, 13.6 Hz, 2H), 3.12 (br t, J=7.6Hz, 1H) 3.05-2.94 (m, 1H), 2.92-2.77 (m, 3H), 2.76-2.65 (m, 2H), 2.51(s, 3H), 2.35-2.26 (m, 1H), 2.14-2.06 (m, 1H), 1.92-1.74 (m, 3H), 1.52(s, 9H).

Step B:2-[4-[7(7-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.A mixture of tert-butyl2-(cyanomethyl)-4-[7-(7-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(100 mg, 159 umol, 1 eq) and TFA (363 mg, 3.19 mmol, 236 uL, 20 eq) wasstirred at 18° C. for 1 hour. The reaction mixture was concenrated undervacuum to give2-[4-[7-(7-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(120 mg, crude, 2 TFA) as brown oil.

Step C:2-[4-[7-(7-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To the solution of2-[4-[7-(7-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(120 mg, 159 umol, 1 eq, 2 TFA), DIEA (205 mg, 1.59 mmol, 276 uL, 10 eq)in DCM (2.5 mL) was added prop-2-enoyl prop-2-enoate (24.0 mg, 190 umol,1.2 eq) at 0° C. and stirred at 18° C. for 1 hour. Water (5 mL) wasadded into the mixture. The resulting mixture was extracted with DCM(3×5 mL). The combined organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated under vacuum. The residue was purified byprep-HPLC (column: Gemini 150*25 5 u; mobile phase: [water (0.05%ammonia hydroxide v/v)-ACN]; B %: 45%-75%, 10 min) to give titlecompound2-[4-[7-(7-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(106 mg, 17.8 umol, two steps 11.2% yield, 97.6% purity) as off-whitesolid. LCMS [ESI, M+1]: 582.

¹H NMR (400 MHz, chloroform-d) δ=7.70 (d, J=8.8 Hz, 1H), 7.63 (d, J=8.8Hz, 1H), 7.17 (dd, J=2.4, 8.8 Hz, 1H), 7.09 (d, J=2.0 Hz, 1H), 7.03 (d,J=2.4 Hz, 1H), 6.97 (dd, J=2.4, 8.8 Hz, 1H), 6.57 (br d, J=10.4 Hz, 1H),6.43-6.36 (m, 1H), 5.83 (br d, J=10.8 Hz, 1H), 5.09 (br s, 1H),4.52-4.31 (m, 3H), 4.25-4.15 (m, 1H), 4.08 (br d, J=12.4 Hz, 1H), 3.96(br s, 1H), 3.92 (s, 3H), 3.72 (br d, J=12.4 Hz, 1H), 3.54 (br d, J=5.6Hz, 2H), 3.30 (br d, J=12.4 Hz, 1H), 3.22-2.95 (m, 3H), 2.93 (d, J=8.4Hz, 1H), 2.86 (br d, J=4.8 Hz, 2H), 2.79-2.65 (m, 1H), 2.51 (s, 3H),2.36-2.26 (m, 1H), 2.16-2.02 (m, 1H), 1.91-1.67 (m, 4H).

Example 289

2-[4-[7-(1-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: tert-butyl2-cyanomethyl)-4-[7(1-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.A mixture of tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.20 g, 424 umol, 1.00 eq), 1-bromoisoquinoline (132 mg, 636 umol, 1.50eq) and DIEA (109 mg, 848 umol, 148 uL, 2.00 eq) in DMSO (4.00 mL) wasstirred at 110° C. for 3 hours. The mixture was diluted with water (5.00mL), extracted with ethyl acetate (3-5.00 mL). The organic layers werewashed with brine (1×10.0 mL), dried over Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by reversed phaseflash [water (FA, 0.10%)/acetonitrile]. The desired fractions werecollected and adjust pH>7 with saturated sodium bicarbonate solution(6.00 mL), and extracted with ethyl acetate (3×20.0 mL). The organiclayers were washed brine (1×30.0 mL), dried over Na₂SO₄, filtered andconcentrated under vacuum to give tert-butyl2-(cyanomethyl)-4-[7-(1-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.15 g, 233 umol, 54.9% yield) as a yellow solid. LCMS [ESI, M+1]: 599.

¹H NMR (400 MHz, chloroform-d) δ=8.17-8.11 (m, 2H), 7.78 (d, J=8.0 Hz,1H), 7.64 (t, J=7.2 Hz, 1H), 7.57-7.51 (m, 1H), 7.28 (s, 1H), 4.69-4.55(m, 3H), 4.42-4.35 (m, 1H), 4.15-4.01 (m, 3H), 3.96-3.81 (m, 2H), 3.57(ddd, J=4.0, 8.0, 16.8 Hz, 1H), 3.27 (dd, J=4.0, 13.6 Hz, 1H), 3.18-3.16(m, 1H), 3.16-2.95 (m, 3H), 2.91-2.73 (m, 3H), 2.70-2.62 (m, 1H), 2.48(s, 3H), 2.34-2.24 (m, 1H), 2.07-2.01 (m, 1H), 1.91-1.73 (m, 3H), 1.52(s, 9H).

Step B:2-[4-[7-(1-isoquinolyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.A mixture of tert-butyl2-(cyanomethyl)-4-[7-(1-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5l-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.15 g, 250.53 umol, 1.00 eq) and TFA (428 mg, 3.76 mmol, 278 uL, 15.0eq) in dichloromethane (0.40 mL) was stirred at 15° C. for 1 hour. Themixture was concentrated under vacuum to give2-[4-[7-(1-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(153 mg, crude, TFA) as a black oil and used into next step withoutfurther purification. LCMS [ESI, M+1]: 499.

Step C:2-[4-[7-(1-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[4-[7-(1-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(153 mg, crude, TFA) and TEA (253 mg, 2.50 mmol, 348 uL) indichloromethane (4.00 mL) was added prop-2-enoyl prop-2-enoate (31.5 mg,250 umol) at 0° C., then stirred at 15° C. for 1 hour. The mixture wasquenched with saturated sodium bicarbonate solution (1.00 mL) andconcentrated under vacuum. The residue was purified by prep-HPLC column:(Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225%,FA)-ACN]; B %: 10%-24%, 7 min) and (column: Phenomenex Synergi C18150*25*10 um; mobile phase: [water (0.225%, FA)-ACN]; B %: 10%-24%, 7min). The desired fractions were collected and lyophilized to give titlecompound2-[4-[7-(1-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(31.2 mg, 52.1 umol, two steps 20.9% yield, FA) as a yellow solid. LCMS[ESI, M+1]: 553.

¹H NMR (400 MHz, acetic) δ=8.44 (d, J=8.4 Hz, 1H), 8.04-7.95 (m, 2H),7.89 (d, J=6.4 Hz, 1H), 7.82 (br t, J=6.8 Hz, 1H), 7.49 (d, J=6.8 Hz,H), 6.91-6.69 (m, 1H), 6.37 (br d, J=16.4 Hz, 1H), 5.87 (br d, J=9.2 Hz,1H), 5.10 (br s, 2H), 4.78 (br s, 3H), 4.53 (br d, J=10.8 Hz, 1H), 4.32(br d, J=12.8 Hz, 1H), 4.13 (br s, 3H), 3.90 (br s, 2H), 3.79-3.40 (m,3H), 3.26 (br s, 3H), 3.12 (br s, 3H), 3.07-2.84 (m, 2H), 2.45-2.34 (m,1H), 2.23-2.09 (m, 3H).

Example 290

2-[4-[7-(6-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Insert: (6-fluoro-1-naphthyl) trifluoromethanesulfonate. To a solutionof 6-fluoronaphthalen-1-ol (0.10 g, 617 umol, 1.00 eq) and DIEA (159 mg,1.23 mmol, 215 uL, 2.00 eq) in dichloromethane (3.00 mL) was addedtrifluoromethylsulfonyl trifluoromethanesulfonate (191 mg, 678 umol, 112uL, 1.10 eq) at 0° C. After stirred at 0° C. for 1 hour, the mixture wasdiluted with water (5.00 mL) and extracted with dichloromethane (3×5.00mL). The organic layers were washed with brine (1×5.00 mL), dried overNa₂SO₄, filtered and concentrated under vacuum. The residue was purifiedby column chromatography (SiO₂, petroleum ether/ethyl acetate=3/1) togive (6-fluoro-1-naphthyl) trifluoromethanesulfonate (0.17 g, 543 umol,88.1% yield) as a colorless oil.

¹H NMR (400 MHz, chloroform-d) δ=8.10 (dd, J=5.2, 8.8 Hz, 1H), 7.83 (d,J=8.4 Hz, 1H), 7.58-7.50 (m, 2H), 7.48-7.40 (m, 2H).

Step A: tert-butyl2-(cyanomethyl)-4-[7-(6-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.A mixture of tert-butyl2-(cyanomethyl)-4-[2-[(1-methylpyrolidin-2-yl)methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.20 g, 424 umol, 1.00 eq), (6-fluoro-1-naphthyl)trifluoromethanesulfonate (150 mg, 509 umol, 1.20 eq), RuPhos (39.6 mg,84.8 umol, 0.20 eq), Pd₂(dba)₃ (38.8 mg, 42.4 umol, 0.10 eq) and Cs₂CO₃(415 mg, 1.27 mmol, 3.00 eq) in toluene (2.00 mL) was stirred at 110° C.for 3 hours under Ni. The mixture was diluted with water (5.00 mL),extracted with ethyl acetate (3×5.00 mL). The organic layers were washedwith brine (1×10.0 mL), dried over Na₂SO₄, filtered and concentratedunder vacuum. The residue was purified by reversed phase flash [water(FA, 0.10%)/acetonitrile]. The desired fractions were collected andadjust pH>7 with saturated sodium bicarbonate solution (5.00 mL), andthen extracted with ethyl acetate (3×20.0 mL), the organic layers werewashed brine (1×30.0 mL), dried over Na₂SO₄, filtered and concentratedunder vacuum to give tert-butyl2-(cyanomethyl)-4-[7-(6-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.20 g, 322 umol, 75.8% yield) as a yellow solid. LCMS [ESI, M+1]: 616.

¹H NMR (400 MHz, chloroform-d) δ=8.22 (dd, J=5.6, 9.2 Hz, 1H), 7.57-7.52(m, 1H), 7.48-7.42 (m, 2H), 7.29-7.24 (m, 1H) 7.10 (d, J=7.6 Hz, 1H),4.62 (br s, 1H) 4.39 (dd, J=4.8, 10.4 Hz, 1H), 4.31-4.22 (m, 2H),4.14-4.00 (m, 3H), 3.95 (br d, J=12.8 Hz, 1H), 3.44 (br s, 1H),3.35-3.25 (m, 2H), 3.23-2.90 (m, 4H), 2.86-2.63 (m, 4H), 2.49 (s, 3H),2.33-2.24 (m, 1H), 2.13-2.00 (m, 1H) 1.89-1.74 (m, 3H), 1.53 (s, 9H).

Step B:2-[4-[7-(6-fluoro-1-naphthyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.A mixture of tert-butyl2-(cyanomethyl)-4-[7-(6-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.20 g, 322 umol, 1.00 eq) and TFA (556 mg, 4.87 mmol, 361 uL, 15.0 eq)in dichloromethane (0.40 mL) was stirred at 15° C. for 1 hour. Themixture was concentrated under vacuum to give2-[4-[7-(6-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(205 mg, crude, TFA) as a black oil and used into next step withoutfurther purification. LCMS [ESI, M+1]: 516.

Step C:2-[4-[7-(6-fluoro-1-naphthyl)-2-[[2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[4-[7-(6-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(205 mg, crude, TFA) and TEA (328 mg, 3.24 mmol, 451 uL) indichloromethane (4.00 mL) was added prop-2-enoyl prop-2-enoate (40.9 mg,324 umol) at 0° C., then stirred at 15° C. for 1 hour. The mixture wasquenched with saturated sodium bicarbonate solution (1.00 mL) andconcentrated under vacuum. The residue was purified by prep-HPLC(column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water(0.225%, FA)-ACN]; B %: 17%-44%, 9 min). The desired fractions werecollected and lyophilized to give title compound2-[4-[7-(6-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(85.6 mg, 139 umol, 42.8% yield, FA) as a off-white solid. LCMS [ESI,M+1]: 570.

¹H NMR (400 MHz, acetic) δ=8.28 (dd, J=5.6, 9.2 Hz, 1H), 7.60 (d, J=8.0Hz, 1H), 7.55-7.45 (m, 2H), 7.31 (dt, J=2.4, 8.8 Hz, 1H), 7.18 (d, J=7.2Hz, 1H), 6.94-6.68 (m, 1H), 6.38 (br d, J=16.8 Hz, 1H), 5.87 (br d,J=10.0 Hz, 1H), 5.16 (br s, 1H), 4.84 (br s, 2H), 4.74-4.54 (m, 1H),4.42 (br d, J=12.8 Hz, 1H), 4.33 (br s, 2H), 4.25-4.08 (m, 1H), 3.92 (brs, 2H), 3.81-3.47 (m, 3H), 3.46-3.16 (m, 4H), 3.11 (br s, 3H), 3.08-2.87(m, 3H), 2.46-2.32 (m, 1H), 2.25-2.11 (m, 3H).

Example 291

2-[4-[7-(4-isoquinolyl)-2-[[(2S)-1-methylpyrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: tert-butyl2-(cyanomethyl)-4-[7-(4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.A mixture of tert-butyl2-(cyanomethyl)-4-[2-[[2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.15 g, 318 umol, 1.00 eq), 4-bromoisoquinoline (99.3 mg, 477 umol,1.50 eq), RuPhos (29.7 mg, 63.6 umol, 0.20 eq), Pd₂(dba)₃ (29.1 mg, 31.8umol, 0.10 eq) and Cs₂CO₃ (311 mg, 954 umol, 3.00 eq) in toluene (5.00mL) was stirred at 10° C. for 3 hours under N₂. The mixture was dilutedwith water (6.00 mL), extracted with ethyl acetate (3×5.00 mL). Theorganic layers were washed with brine (I 10.0 mL), dried over Na₂SO₄,filtered and concentrated under vacuum. The residue was purified byreversed phase flash [water (FA, 0.1%)/acetonitrile]. The desiredfractions were collected and adjust pH>7 with saturated sodiumbicarbonate solution (5.00 mL), and extracted with ethyl acetate (3×20.0mL). The combined organic layers were washed brine (1×30.0 mL), driedover Na₂SO₄, filtered and concentrated under vacuum to give tert-butyl2-(cyanomethyl)-4-[7-(4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.17 g, 273 umol, 85.9% yield) as a yellow solid. LCMS [ESL M+1]: 599.

¹H NMR (400 MHz, chloroform-d) δ=9.03 (s, 1H), 8.26 (s, 1H), 8.14 (d,J=8.4 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.73 (dt, J=1.2, 7.2 Hz, 1H),7.67-7.60 (m, 1H), 4.63 (br s, 1H), 4.44-4.31 (m, 3H), 4.15-4.03 (m,2H), 3.95 (br d, J=12.8 Hz, 1H), 3.59-3.49 (m, 1H), 3.40 (br d, J=7.2Hz, 1H), 3.34-3.19 (m, 2H), 3.18-2.93 (m, 4H), 2.90-2.79 (m, 2H),2.77-2.66 (m, 2H), 2.50 (s, 3H), 2.35-2.24 (m, 1H), 2.10-2.02 (m, 1H),1.92-1.79 (m, 3H), 1.52 (s, 9H).

Step B:2-[4-[7-(4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.A mixture of tert-butyl2-(cyanomethyl)-4-[7-(4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.15 g, 251 umol, 1.00 eq) and TFA (428 mg, 3.76 mmol, 278 uL, 15.0 eq)in dichloromethane (0.30 mL) was stirred at 15° C. for 0.5 h. Themixture was concentrated under vacuum to give2-[4-[7-(4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(153 mg, crude, TFA) as a black oil and used into next step withoutfurther purification. LCMS [ESI, M+1]: 499.

Step C:2-[4-[7-(4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[4-[7-(4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(153 mg, crude, TFA) and Et₃N (254 mg, 2.51 mmol, 349 uL) indichloromethane (2.00 mL) was added prop-2-enoyl prop-2-enoate (31.6 mg,251 umol) at −40° C. After stirred at 15° C. for 1 hour, the mixture wasquenched with saturated sodium bicarbonate solution (0.10 mL) andconcentrated under vacuum. The residue was purified by columnchromatography (Al₂O₃, methanol/ethyl acetate=1/1) and prep-HPLC(column: Boston Green ODS 150*30 5 u; mobile phase: [water (0.225%,FA)-ACN]; B %: 12%-36%, 10 min). The desired fractions were collectedand lyophilized to give title compound2-[4-[7-(4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(28.3 g, 43.4 umol, two steps 17.3% yield, FA) as a yellow solid. LCMS[ESI, M+1]: 553.

¹H NMR (400 MHz, acetic) δ=9.45 (s, 1H), 8.51-8.36 (m, 3H), 8.17 (br t,J=8.0 Hz, 1H), 8.03-7.97 (m, 1H), 6.92-6.67 (m, 1H), 6.37 (br d, J=16.0Hz, 1H), 5.87 (br d, J=10.0 Hz, 1H), 5.14 (br s, 1H), 4.82 (br s, 2H),4.66-4.48 (m, 3H), 4.40 (br d, J=12.0 Hz, 1H), 4.22-3.80 (m, 3H),3.79-3.49 (m, 4H), 3.32-3.09 (m, 71H), 3.07-2.88 (m, 2H), 2.47-2.36 (m,1H), 2.24-2.11 (m, 3H).

Example 292

2-[4-[7-(5-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: tert-butyl2-(cyanomethyl)-4-[7-(5-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.tert-butyl2-(cyanomethyl)-4-[2-[(I-methylpyrrolidin-2-yl)methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 424 umol, 1.00 eq), 5-bromoisoquinoline (115 mg, 551 umol, 1.30eq), RuPhos (39.6 mg, 84.8 umol, 0.20 eq), Cs₂CO₃ (415 mg, 1.27 mmol,3.00 eq) and Pd₂(dba)₃ (38.8 mg, 42.4 umol, 0.10 eq) in toluene (6.00mL) was de-gassed and then heated to 90° C. for 12 hours under N₂. Uponcompletion, the reaction mixture was filtered and the filtrate wasconcentrated. The residue was purified by reversed-phase flash [water(0.1% FA)/acetonitrile] to give tert-butyl2-(cyanomethyl)-4-[7-(5-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(217 mg, 344 umol, 81.0% yield, 94.8% purity) as a yellow solid. LCMS[ESI, M+1]: 599.

Step B:2-[4-[7-(5-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.A solution of tert-butyl2-(cyanomethyl)-4-[7-(5-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(217 mg, 362 umol, 1.00 eq) in TFA (620 mg, 5.44 mmol, 403 uL, 15.0 eq)was stirred at 25° C. for 1 hour. Upon completion, the reaction mixturewas concentrated under vacuum to give2-[4-[7-(5-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(222 mg, crude, TFA) as a yellow oil which was used directly in the nextstep without further purification. LCMS [ESI, M+1]: 499.

Step C:2-[4-[7-(5-isoquinolyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[4-[7-(5-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(222 mg, 362 umol, TFA) and TEA (367 mg, 3.62 mmol, 504 uL) in DCM (4.50mL) was added prop-2-enoyl prop-2-enoate (45.7 mg, 362 umol) dropwise at0° C. The mixture was stirred at 25° C. for 1 hour. Upon completion, thereaction was quenched by MeOH (0.5 mL), diluted with water (2 mL) andextracted with EtOAc (2×5 mL). The organic layers were dried over Na₂SO₄and concentrated under vacuum. The residue was purified by prep-HPLC(column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water(0.225% FA)-ACN]; B %: 4%-20%, 8 min) and lyophilized to give titlecompound2-[4-[7-(5-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(73.0 mg, 117 umol, two steps 32.2% yield, 95.6% purity, FA) as a yellowsolid LCMS [ESI, M+1]:553.

¹H NMR (400 MHz, Acetic) δ=9.71 (s, 1H), 8.69 (d, J=6.4 Hz, 1H), 8.53(d, J=6.8 Hz, 1H), 8.15 (d, J=8.0 Hz, 1H), 7.91 (t, J=7.8 Hz, 1H), 7.78(d, J=7.2 Hz, 1H), 6.97-6.68 (m, 1H), 6.38 (br d, J=16.8 Hz, 1H), 5.87(br d, J=10.4 Hz, 1H), 5.15 (br s, 1H), 4.81 (br d, J=4.4 Hz, 2H),4.67-4.51 (m, 1H), 4.49-4.31 (m, 3H), 4.28-4.04 (m, 1H), 3.91 (br s,2H). 3.78-3.64 (m, 1H), 3.63-3.37 (m, 4H), 3.36-3.20 (m, 1H), 3.11 (brs, 5H), 3.08-2.86 (m, 2H), 2.46-2.33 (m, 1H), 2.24-2.10 (m, 3H).

Example 293

2-[1-[(E)-but-2-enoyl]-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

Step A: tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.A mixture of tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(100 mg, 212 umol, 1.0 eq), Pd₂(dba)₃ (19.4 mg, 21.2 umol, 0.10 eq),RuPhos (14.8 mg, 31.8 umol, 0.15 eq) and Cs₂CO₃ (207 mg, 636 umol, 3.0eq) in toluene (3.0 mL) was dropwise added 1-bromonaphthalene (65.9 mg,318 umol, 44.2 uL, 1.5 eq). The reaction mixture was degassed and purgedwith N₂ for 3 times, and the mixture was stirred at 110° C. for 4 hoursunder N₂ atmosphere. The reaction was washed with water (20.0 mL). Theaqueous phase was extracted with ethyl acetate (20.0 mL×3). Combineextracts were washed with brine (50.0 mL), dried with Na₂SO₄ the solventwas then removed under vacuum. The residue was purified by reversedphase flash (C18, 0.1% FA in water, 0-80% MeCN). Compound tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(80.0 mg, 116 umol, 54.6% yield) was obtained as a off-white solid. LCMS[ESI, M+1]: 598.

Step B:2-[4-[2[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(80.0 mg, 134 umol, 1.0 eq) in DCM (2.0 mL) was added TFA (3.08 g, 27.0mmol, 2.0 mL, 202 eq). The mixture was stirred at 20° C. for 30 minunder Ni atmosphere. The organic solvent was removed under vacuum. Thecrude product2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(110 mg, crude, 2 TFA) was obtained as a yellow oil and was used intothe next step without further purification. LCMS [ESI, M+1]:498.

Step C:2-[1-[(E)-but-2-enoyl]4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-S5f-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(110 mg, 152 umol, 2 TFA) in DCM (2.00 mL) was added DIEA (100 mg, 774umol, 135 uL) and (E)-but-2-enoyl chloride (35.0 mg, 335 umol, 32.1 uL)at 0° C. The mixture was stirred at 0° C. for 1 hour. The reaction wasquenched with water (10.0 mL). The crude mixture was extracted withethyl acetate (20.0 mL×3). Combine extracts were washed with brine (50.0mL), dried with Na₂SO₄ the solvent was then removed under vacuum. Theresidue was purified by prep-HPLC (column: Boston Green ODS 150*30 5 u;mobile phase. [water (0.225% FA)-ACN]; B %: 20%-50%, 10 min) andlyophilization. Title compound2-[1-[(E)-but-2-enoyl]-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(13.3 mg, 23.4 umol, 99.7% purity, FA) vas obtained as a white solid.LCMS [ESI, M+1]: 566.

¹H NMR (400 MHz, Chloroform-d) δ 8.37 (s, 1H), 8.14-8.13 (m, 1H),7.80-7.78 (m, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.46-7.42 (m, 2H), 7.36 (m,1H), 7.07 (d, J=7.6 Hz, 1H), 6.95-6.90 (m, 1H), 6.22 (d, J=15.6 Hz, 1H),5.05-4.91 (br, 1H), 4.67-4.63 (m, 1H), 4.37-4.32 (m, 1H), 4.24-4.20 (m,2H), 4.12 (d, J=14.8 Hz, 1H), 3.96 (d, J=11.6 Hz, 1H), 3.51-3.49 (m,1H), 3.39-3.29 (m, 2H), 3.18-3.12 (m, 7H), 2.90-2.76 (m, 2H), 2.71 (s,3H), 2.65-2.58 (m, 1H), 2.18-2.12 (m, 1H), 2.00-1.95 (m, 1H), 1.90-1.86(m, 5H).

Example 294

2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(5-quinolyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(5-quinolyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.tert-butyl2-(cyanomethyl)-4-[2-[(1-methylpyrrolidin-2-yl)methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 424 umol, 1.00 eq), 5-bromoquinoline (115 mg, 551 umol, 1.30eq), RuPhos (39.6 mg, 84.8 umol, 0.20 eq), Cs₂CO₃ (415 mg, 1.27 mmol,3.00 eq) and Pd₂(dba)₃ (38.8 mg, 42.4 umol, 0.10 eq) in toluene (6.00mL) was de-gassed and then heated to 90° C. for 12 hours under N₂. Uponcompletion, the reaction mixture was filtered and the filtrate wasconcentrated. The residue was purified by reversed-phase flash [water(0.1% FA)/acetonitrile] to give tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(5-quinolyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 315 umol, 74.4% yield, 94.4% purity) as a brown oil. LCMS [ESI,M+1]: 599.

Step B: 2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(5-quinolyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.A solution of tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(5-quinolyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 334 umol, 1.00 eq) in TFA (571 mg, 5.01 mmol, 371 uL, 15.0 eq)was stirred at 25° C. for 1 hour. Upon completion, the reaction mixturewas concentrated under vacuum to give2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(5-quinolyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(204 mg, crude, TFA) as a yellow oil which was used directly in the nextstep without further purification. LCMS [ESI, M+1]: 499.

Step C:2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(5-quinolyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(5-quinolyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(204 mg, 333 umol, 1.00 eq, TFA) and TEA (337 mg, 3.33 mmol, 463 uL) inDCM (4.00 mL) was added prop-2-enoyl prop-2-enoate (42.0 mg, 333 umol)dropwise at 0° C. The mixture was stirred at 25° C. for 1 hour. Uponcompletion, the reaction was quenched with MeOH (0.5 mL), diluted withwater (2 mL) and extracted with EtOAc (2×5 mL). The organic layers weredried over Na₂SO₄, filtered and concentrated under vacuum. The residuewas purified by prep-TLC (DCM/MeOH 8/1) and prep-HPLC (column: BostonGreen ODS 150*30 5 u; mobile phase. [water (0.225% FA)-ACN]; B %:7%-34%, 10 min). The desired fractions were collected and lyophilized togive title compound2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(5-quinolyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(49.1 mg, 79.5 umol, two steps 23.9% yield, 96.9% purity, FA) as ayellow solid. LCMS [ESI, M+1]: 553.

¹H NMR (400 MHz, Acetic) δ=9.22 (d, J=4.8 Hz, 1H), 9.15 (d, J=8.4 Hz,1H), 8.09 (d, J=8.8 Hz, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.96-7.90 (m, 1H),7.50 (d, J=7.6 Hz, 1H), 6.98-6.71 (m, 1H), 6.37 (br d, J=17.2 Hz, 1H),5.88 (br d, J=10.4 Hz, 1H), 5.15 (br s, 1H), 4.81 (br s, 2H), 4.77-4.52(m, 1H), 4.50-4.33 (m, 3H), 4.14 (br d, J=12.4 Hz, 1H), 3.91 (br s, 2H),3.79-3.66 (m, 1H), 3.65-3.32 (m, 4H), 3.12 (br s, 6H), 3.05 (br d,J=16.8 Hz, 2H), 2.46-2.34 (m, 1H), 2.23-2.09 (m, 3H).

Example 295

2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(4-quinolyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A:[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(4-quinolyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.A mixture of tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(Intermediate 66, 0.15 g, 318 umol, 1.00 eq), 4-bromoquinoline (99.3 mg,477 umol, 1.50 eq), RuPhos (29.7 mg, 63.6 umol, 0.20 eq), Pd₂(dba)₃(29.1 mg, 31.8 umol, 0.10 eq) and Cs₂CO₃ (311 mg, 954 umol, 3.00 eq) intoluene (5 mL) was stirred at 100° C. for 3 hours under N₂. The mixturewas diluted with water (5.00 mL), extracted with ethyl acetate (3-5.00mL). The organic layers were washed with brine (1×10.0 mL), dried overNa₂SO₄, filtered and concentrated under vacuum. The residue was purifiedby reversed phase flash [water (FA, 0.1%)/acetonitrile]. The desiredfractions were collected and adjust pH>7 with saturated sodiumbicarbonate (5.00 mL) and extracted with ethyl acetate (3×20.0 mL). Theorganic layers were washed brine (1×30.0 mL), dried over Na₂SO₄,filtered and concentrated under vacuum to give tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(4-quinolyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.17 g, 269 umol, 84.8% yield) as a yellow solid. LCMS [ESI, M+1]: 599.

¹H NMR (400 MHz, chloroform-d) δ=8.77 (d, J=4.8 Hz, 1H), 8.07 (dd,J=8.0, 16.0 Hz, 2H), 7.70 (dt, J=1.2, 7.2 Hz, 1H), 7.56-7.50 (m, 1H),6.92 (d, J=4.8 Hz, 1H), 4.62 (br s, 1H), 4.44-4.33 (m, 3H), 4.15-4.04(m, 2H), 3.95 (br d, J=12.0 Hz, 1H), 3.74-3.64 (m, 1H), 3.46 (br d,J=7.2 Hz, 1H), 3.37-3.21 (m, 2H), 3.18-2.93 (m, 4H), 2.93-2.79 (m, 2H),2.72 (br dd, J=6.0, 16.8 Hz, 2H), 2.51 (s, 3H), 2.36-2.26 (m, 1H),2.13-2.06 (m, 1H), 1.93-1.79 (m, 3H), 1.53 (s, 9H).

Step B:2-[4-[2[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(4-quinolyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.A mixture of tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(4-quinolyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(165 mg, 276 umol, 1.00 eq) and TFA (471 mg, 4.13 mmol, 306 uL, 15.0 eq)in dichloromethane (0.30 mL) was stirred at 15° C. for 0.5 hour. Themixture was concentrated under vacuum to give2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(4-quinolyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(168 mg, crude, TFA) as a black oil and used into next step withoutfurther purification. LCMS [ESI, M+1]: 499.

Step C:2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(4-quinolyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(4-quinolyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(168 mg, crude, TFA) and Et₃N (277 mg, 2.74 mmol, 382 uL) indichloromethane (3.00 mL) was added prop-2-enoyl prop-2-enoate (34.6 mg,274.22 umol) at −40° C. After stirred at 15° C. for 1 hour, the mixturewas quenched with saturated sodium bicarbonate (0.10 mL) andconcentrated under vacuum. The residue was purified by columnchromatography (Al₂O₃, methanol/ethyl acetate=1/1) and prep-HPLC(column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water(0.225%, FA)-ACN]; B %: 1%-21%, 7 min). The desired fractions werecollected and lyophilized to give2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(4-quinolyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 295, 23.4 mg, 39.6 umol, two steps 13.4% yield, 93.6% purity,FA) as a yellow oil. LCMS [ESI, M+1]: 553.

SFC condition: OD-3S_3_40_3 ML Column: Chiralcel OD-3 100×4.6 mm I.D., 3um, mobile phase: 40% methanol (0.05% DEA) in CO₂, flow rate: 3 mL/min,wavelength: 220 nm.

¹H NMR (400 MHz, acetic) δ=8.65 (d, J=7.2 Hz, 1H), 8.35 (d, J=8.4 Hz,1H), 8.15 (s, 1H), 7.99 (t, J=7.2 Hz, 1H), 7.77 (t, J=7.6 Hz, 1H), 7.28(d, J=6.8 Hz, 1H), 6.74 (dd, J=10.8, 16.8 Hz, 1H), 6.32 (dd, J=1.2, 16.8Hz, 1H), 5.85 (dd, J=1.2, 10.8 Hz, 1H), 5.01 (br s, 1H), 4.85-4.74 (m,2H), 4.42 (br d, J=14.0 Hz, 1H), 4.35-4.19 (m, 3H), 4.16-3.76 (m, 4H),3.66 (br d, J=14.0 Hz, 2H), 3.51-3.40 (m, 1H), 3.39-3.16 (m, 4H), 3.13(s, 3H), 3.07-2.90 (m, 2H), 2.49-2.39 (m, 1H), 2.26-2.17 (m, 3H).

Example 296

2-[4-[2-[2-(dimethylamino)ethoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: tert-butyl2-(cyanomethyl)-4-[2-[2-(dimethylamino)ethoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of tert-butyl2-(cyanomethyl)-4-[2-methylsulfinyl-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(150 mg, 266 umol, 1.0 eq) and 2-(dimethylamino)ethanol (47.4 mg, 531umol, 53.3 uL, 2.0 eq) in toluene (1.0 mL) was added t-BuONa (51.1 mg,531 umol, 2.0 eq). The mixture was stirred at 0° C. for 0.5 hour. Aftercompletion, the mixture was added water (10.0 mL) and extracted with EA(10 mL×3). The organic layer was dried over Na₂SO₄, filtered andconcentrated. The obtained product was purified by reversed phase flashcolumn (C18, 0.1% FA in water, 0-40% MeCN). The desired fraction wascollected and adjusted with saturated NaHCO₃ aqueous to pH˜7, thenconcentrated under vacuum. The remained liquid was extracted with EA (10mL×3). The organic layer was dried over Na₂SO₄, filtered andconcentrated. The product tert-butyl2-(cyanomethyl)-4-[2-[2-(dimethylamino)ethoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(150 mg, 254 umol, 95.8% yield) was obtained as yellow oil. LCMS [ESI,M+1]: 590.

Step B:2-[4-[2-[2-(dimethylamino)ethoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl2-(cyanomethyl)-4-[2-[2-(dimethylamino)ethoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(150 mg, 254 umol, 1.0 eq) in DCM (1.0 mL) was added TFA (29.0 mg, 254umol, 18.8 uL, 1.0 eq). The mixture was stirred at 0° C. for 0.5 hour.After completion, the mixture was concentrated under vacuum. The residuewas added saturated NaHCO₃ aqueous (5 mL) and extracted with DCM (10mL×3). The organic layer was dried over Na₂SO₄, filtered andconcentrated to give2-[4-[2-[2-(dimethylamino)ethoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(200 mg, crude) as yellow oil. LCMS [ESI, M+1]: 490.

Step C: To a solution of2-[4-[2-[2-(dimethylamino)ethoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(125 mg, 255 umol, 1.0 eq) and DIEA (198 mg, 1.53 mmol, 267 uL, 6.0 eq)in DCM (1.00 mL) was added prop-2-enoyl prop-2-enoate (32.2 mg, 255umol, 1.0 eq) at 0° C. The mixture was stirred at 0° C. for 0.5 hour.After completion, the mixture was concentrated under vacuum. Theobtained product was purified by prep-HPLC (column: Phenomenex SynergiC18 150*30 mm*4 um; mobile phase: [water (0.225% FA)-ACN]; B %: 10%-40%,10 min). Then concentrated and lyophilized. The product2-[4-[2-[2-(dimethylamino)ethoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 296, 30.7 mg, 51.8 umol, 20.3% yield, 99.5% purity, FA) wasobtained as white solid. LCMS [ESI, M+1]: 544.

¹H NMR (400 MHz, Chloroform-d) δ 8.45 (br s, 1H), 7.67 (br d, J=8.0 Hz,1H), 7.57 (t, =7.2 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.30 (d, J=7.6 Hz,1H), 6.71-6.49 (m, 1H), 6.47-6.29 (m, 1H), 5.82 (br d, J=10.4 Hz, 1H),5.07-4.97 (m, 1H), 4.54 (t, J=5.4 Hz, 2H), 4.12 (br d, J=13.6 Hz, 1H),4.07 (s, 2H), 3.98 (br d, J=12.0 Hz, 1H), 3.40-3.30 (m, 2H), 3.22-3.09(m, 4H), 3.05 (t, J=5.4 Hz, 2H), 2.92 (dd, J=8.0, 16.8 Hz, 1H),2.86-2.81 (m, 1H), 2.79-2.70 (m, 2H), 2.56 (s, 6H).

Example 297

2-(1-acryloyl-4-(2-(((R)-1-methylpyrrolidin-3-yl)methoxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: tert-butyl 2-(cyanomethyl)-4-[2-[3-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of tert-butyl2-(cyanomethyl)-4-[2-methylsulfinyl-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 354 umol, 1.0 eq) and3-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propan-1-ol(Intermediate 18, 111 mg, 708 umol, 2.0 eq) in toluene (3.0 mL) wasadded t-BuONa (68.1 mg, 708 umol, 2.0 eq) at 0° C., the reaction wasstirred at 0° C. for 0.5 hour. After completion, the reaction mixturewas added water (10 mL), then extracted with EA (2×10 mL), the combinedorganic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by reversed phase flash (C18, 60% MeCN in water),the obtained product was adjusted with saturated NaHCO₃ aqueous to pH˜8,then concentrated, extracted with EA (2×10.0 mL), the combined organiclayer was dried over Na₂SO₄, filtered and concentrated to givetert-butyl 2-(cyanomethyl)-4-[2-[3-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(130 mg, 197 umol, 55.7% yield, 99.8% purity) as white solid. LCMS [ESI,M+1]: 658.

Step B:2-[4-[2-[3-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a mixture of tert-butyl2-(cyanomethyl)-4-[2-[3-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(70.0 mg, 106 umol, 1.0 eq) in DCM (0.5 mL) was added TFA (770 mg, 6.75mmol, 0.5 mL, 63.5 eq). The reaction mixture was stirred at 20° C. for0.5 hour. After completion, the reaction mixture was concentrated togive2-[4-[2-[3-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(83.0 mg, crude, 2 TFA) as yellow oil which was used for the next stepwithout further purification. LCMS [ESI, M+1]: 558.

Step C:2-[4-[2-[3-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a mixture of2-[4-[2-[3-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(83.0 mg, 106 umol, 1.0 eq, 2 TFA) in DCM (1.0 mL) was added DIEA (81.9mg, 634 umol, 110 uL, 6.0 eq) and prop-2-enoyl prop-2-enoate (13.3 mg106 umol, 1.0 eq) at 0° C., the reaction mixture was stirred at 20° C.for 0.5 hour. After completion, the reaction mixture was quenched withMeOH (0.5 mL), and concentrated. The residue was purified by prep-HPLC((Instrument: ACSWH-GX-G; Column: Phenomenex Gemini 150*25 mm*10 um;Condition: water (0.225% FA)-ACN; Begin B: 12; End B: 42; Gradient Time(min): 10.5; 100% B Hold Time (min): 2, FlowRate (ml/min): 2), theobtained product was concentrated and then under lyophilization. Theproduct2-[4-[2-[3-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 297, 17.6 mg, 26.3 umol, two steps yield 24.90% yield, 98.1%purity, FA) was obtained as yellow solid. LCMS [ESI, M+1]: 612.

¹H NMR (400 MHz, chloroform-d) δ 7.69 (d, J=7.6 Hz, 1H), 7.59 (t, J=7.6Hz, 1H), 7.42 (d, J=7.6 Hz, 1H), 7.31 (t, J=7.6 Hz, 1H), 6.72-6.52 (m,1H), 6.40 (d, J=16.4 Hz, 1H), 5.84 (br d, J=10.4 Hz, 1H), 5.16-5.02 (m,1H), 4.58-4.51 (m, 1H), 4.38 (br t, J=5.8 Hz, 2H), 4.21 (br d, J=9.2 Hz,1H), 4.18-4.06 (m, 4H), 3.99 (br d, J=11.6 Hz, 1H), 3.74 (br d, J=8.4Hz, 1H), 3.42-3.29 (m, 2H), 3.27-3.04 (m, 6H), 3.04-2.61 (m, 6H),2.28-2.07 (m, 3H), 2.04-1.92 (m, 1H).

Example 298

2-(1-acryloyl-4-(2-(((R)-1-methylpyrrolidin-3-yl)methoxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: [(3R)-1-methylpyrrolidin-3-yl]methanol. To a solution oftert-butyl (3R)-3-(hydroxymethyl) pyrrolidine-1-carboxylate (2.0 g, 9.94mmol, 1.0 eq) in THF (30.0 mL) was added LiAlH₄ (754 mg, 19.9 mmol, 2.0eq) in portions at 0° C. After addition, the reaction was stirred at 70°C. for 3 hours. After completion, the reaction mixture was quenched withsaturated Na₂SO₄ aqueous (2.4 mL), then extracted with Ethyl acetate(100 mL). The organic layer was dried with Na₂SO₄ and filtrated. Thesolvent was removed under vacuum to give[(3R)-1-methylpyrrolidin-3-yl]methanol (1.0 g, crude) as yellow oilwhich was used for the next step without further purification.

¹H NMR (400 MHz, chloroform-d) δ 3.64 (dd, J=4.8, 10.0 Hz, 1H), 3.52(dd, J=5.6, 10.0 Hz, 1H), 2.78-2.67 (m, 1H), 2.60-2.45 (m, 2H),2.42-2.23 (m, 5H), 2.08-1.91 (m, 1H), 1.72-1.57 (m, 1H).

Step B: tert-butyl2-(cyanomethyl)-4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of tert-butyl2-(cyanomethyl)-4-[2-methylsulfinyl-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(100 mg, 177 umol, 1.0 eq) and [(3R)-1-methylpyrrolidin-3-yl]methanol(61.2 mg, 531 umol, 3.0 eq) in toluene (1.0 mL) was added t-BuONa (34.0mg, 354 umol, 2.0 eq) at 0° C., the reaction was stirred at 0° C. for0.5 hour. After completion, the reaction mixture was added water (10.0mL), then extracted with Ethyl acetate (2×10 mL), the combined organiclayer was dried over Na₂SO₄, filtered and concentrated. The residue waspurified by reversed phase flash (C18, 50% MeCN in water). tert-butyl2-(cyanomethyl)-4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(40.0 mg, 63.4 umol, 35.8% yield, 97.6% purity) was obtained as whitesolid. LCMS [ESI, M+1]: 616.

Step C:2-[4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a mixture of tert-butyl2-(cyanomethyl)-4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(40.0 mg, 64.9 umol, 1.0 eq) in DCM (0.5 mL) was added TFA (770 mg, 6.75mmol, 500 uL, 104 eq). The reaction mixture was stirred at 20° C. for0.5 hour. After completion, the reaction mixture was concentrated togive2-[4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(48.0 mg, crude, 2 TFA) as yellow oil which was used for the next stepwithout further purification. LCMS [ESI, M+1]: 516.

Step D:2-[4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a mixture of2-[4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(48.0 mg, 64.6 umol, 1.0 eq, 2 TFA) in DCM (1.0 mL) was added DIEA (25.0mg. 194 umol, 33.7 uL, 3.0 eq) and prop-2-enoyl prop-2-enoate (8.14 mg,64.6 umol, 1.0 eq) at 0° C., the reaction mixture was stirred at 20° C.for 0.5 hour. After completion, the reaction mixture was quenched withmethanol (0.5 mL), and concentrated. The residue was purified byprep-HPLC ((Instrument: ACSWH-GX-M; Column: Gemini 150*25 5 u;Condition: water (0.04% NH₃H₂O)-ACN; Begin B: 60; End B: 81; GradientTime (min): 10; 100% B Hold Time (min): 3; FlowRate (ml/min): 25), theobtained product was concentrated and then under lyophilization to give2-[4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enyl-piperazin-2-yl]acetonitrile(5.48 mg, 9.26 umol, 14.4% yield, 96.3% purity) as brown solid. LCMS[ESI, M+1]: 570.

¹H NMR (400 MHz, chloroform-d) δ 7.61 (d, J=8.0 Hz, 1H), 7.50 (t, J=7.6Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 7.22 (t, J=7.6 Hz, 1H), 6.54-6.44 (m,1H), 6.32 (dd, J=1.6, 16.8 Hz, 1H), 5.75 (br d, J=10.8 Hz, 1H),5.12-4.92 (m, 1H), 4.13 (d, J=1=6.8 Hz, 2H), 4.07-3.97 (m, 3H),3.92-3.84 (m, 1H), 3.62-3.42 (m, 1H), 3.31-3.22 (m, 1H), 3.16-2.95 (m,3H), 2.89-2.49 (m, 7H), 2.47-2.35 (m, 2H), 2.28 (s, 3H), 2.05-1.92 (m,1H), 1.57-1.46 (m, 2H).

Example 299

2-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: tert-butyl2-(cyanomethyl)-4-[2-methylsulfanyl-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate. To asolution of tert-butyl2-(cyanomethyl)-4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(3.70 g, 9.15 mmol, 1.0 eq), Pd₂(dba)₃ (1.26 g, 1.37 mmol, 0.15 eq),RuPhos (854 mg, 1.83 mmol, 0.2 eq) and Cs₂CO3 (7.45 g, 22.9 mmol, 2.50eq) in toluene (74.0 mL) was added 1-bromo-2-(trifluoromethyl)benzene(4.12 g, 18.3 mmol, 2.49 mL, 2.0 eq). The mixture was stirred at 100° C.for 12 hours After completion, the mixture was added water (100 mL) andextracted with Ethyl acetate (100 mL×3). The organic layer was driedover Na₂SO₄, filtered and concentrated. The residue was purified byreversed phase flash column (C18, 0.1% FA in water, 0-90% MeCN). Theproduct tert-butyl2-(cyanomethyl)-4-[2-methylsulfanyl-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1.90 g, 3.46 mmol, 37.8% yield) was obtained as yellow solid.

¹H NMR (400 MHz, Chloroform-d) δ 7.69 (d, J=8.0 Hz, 1H), 7.57 (t, J=7.6Hz, 1H), 7.46-7.37 (m, 2H), 7.22-7.11 (m, 1H), 4.67-4.55 (m, 1H), 4.03(br d, J=13.6 Hz, 2H), 3.88 (br d, J=12.0 Hz, 1H), 3.68-3.47 (m, 1H),3.30-3.08 (m, 4H), 3.02 (dt, J=3.2, 12.4 Hz, 1H), 2.94-2.69 (m, 4H),2.51 (s, 3H), 1.52 (s, 9H).

Step B: tert-butyl2-(cyanomethyl)-4-[2-methylsulfinyl-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of tert-butyl2-(cyanomethyl)-4-[2-methylsulfanyl-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1.50 g, 2.46 mmol, 1.0 eq) in DCM (15.0 mL) was added m-CPBA (593 mg,2.75 mmol, 1.12 eq. 80% purity) at 0° C. The mixture was stirred at 0°C. for 0.5 hour. After completion, the mixture was added saturatedNa₂S₂O; aqueous (30.0 mL) and extracted with ethyl acetate (30.0 mL×3).The organic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by reversed phase flash column (C18, 0.1% FA inwater, 0-90% MeCN) to give tert-butyl2-(cyanomethyl)-4-[2-methylsulfinyl-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1.16 g, 2.05 mmol, 83.6% yield) as yellow solid. LCMS [ESI, M+1]: 565.

Step C: tert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2R)-methylpyrrolidin-2-yl]methoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of tert-butyl(2S)-2-(cyanomethyl)-4-[2-methylsulfinyl-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 354 umol, 1.0 eq) in toluene (3.0 mL) was added[(2R)-1-methylpyrrolidin-2-yl]methanol (81.6 mg, 708.4 umol, 2.0 eq) andt-BuONa (68.1 mg, 708 umol, 2.0 eq) at 0° C. The mixture was stirred at0° C. for 20 min. After completion, the reaction was quenched with water(10.0 mL). The crude mixture was extracted with ethyl acetate (15 mL×3).The combined organic layer were washed with brine (50.0 mL), dried withNa₂SO₄ and filtrated. The solvent was then removed under vacuum. Theresidue was purified by reversed phase flash (C18, 0.1% FA in water,0-80% MeCN). Compound tert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(170 mg, 275 umol, 77.7% yield) was obtained as a white solid. LCMS[ESI, M+1]: 616.

¹H NMR (400 MHz, CHLOROFORM-d) 8.08 (s, 1H), 7.61 (d, J=7.6 Hz, 1H),7.51 (t, J=7.7 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.25-7.19 (m, 1H),5.02-4.78 (m, 1H), 4.58-4.43 (m, 2H), 4.17 (br t, J=12.5 Hz, 1H),4.08-3.86 (m, 5H), 3.64-3.51 (m, 1H), 3.23 (br dd, J=3.8, 13.8 Hz, 1H),3.11-3.01 (m, 3H), 2.96 (s, 3H), 2.84-2.58 (m, 4H), 2.31-2.03 (m, 2H),2.02-1.94 (m, 3H), 1.44 (s, 9H), 1.19 (t, J=7.2 Hz, 1H).

Step D:2-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl2-(cyanomethyl)-4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(170 mg, 276 umol, 1.0 eq) in DCM (1.50 mL) was added TFA (2.31 g, 20.3mmol, 1.50 mL, 73.4 eq). The mixture was stirred at 20° C. for 15 minunder N₂ atmosphere. After completion, the organic solvent was removedunder vacuum. The crude product2-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(240 mg, crude, 2 TFA) was obtained as a yellow oil and used into thenext step without further purification. LCMS [ESI, M+1]: 516.

Step E:2-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-[2-trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(240 mg, 2 TFA) in DCM (3.0 mL) was added prop-2-enoyl prop-2-enoate(40.0 mg, 317 umol) and DIEA (130 mg, 1.01 mmol, 175 uL) at 0° C. Themixture was stirred at 0° C. for 30 mins. The reaction was quenched withwater (20.0 mL). The crude mixture was extracted with ethyl acetate(20.0 mL×3). The combine extracts were washed with brine (50.0 mL),dried with Na₂SO₄ and filtrated. The solvent was then removed undervacuum. The residue was purified by prep-HPLC (column: Phenomenex Gemini150×25 mm×10 um; mobile phase: [water (0.05% ammonia hydroxidev/v)-ACN]; B %: 55%-85%, 3 min). Compound2-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 299, 10.2 mg, 16.8 umol, 94.3% purity) was obtained as a whitesolid. LCMS [ESI, M+]: 570.

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.68 (d, J=7.2 Hz, 1H), 7.58 (t, J=7.6Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H), 6.59 (br s,1H), 6.40 (d, J=16.4 Hz, 1H), 5.83 (d, J=10.4 Hz, 1H), 5.07 (br s, 1H),4.85 (d, J=7.1 Hz, 1H), 4.66-4.39 (m, 1H), 4.20 (d, J=11.1 Hz, 1H),4.13-3.95 (m, 4H), 3.70-3.55 (m, 2H), 3.45-3.20 (m, 2H), 3.16-2.99 (m,3H), 2.98-2.91 (m, 4H), 2.85-2.70 (m, 4H), 2.33-2.14 (m, 2H), 2.10-2.01(m, 2H).

Example 300

2-[4-[2-[2-(diethylamino)ethoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: -tert-butyl2-(cyanomethyl)-4-[2-[2-diethylamino)ethoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of tert-butyl2-(cyanomethyl)-4-[2-methylsulfinyl-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 354 umol, 1.0 eq) and 2-(diethylamino)ethanol (83.0 mg, 708umol, 93.9 uL, 2.0 eq) in toluene (3.0 mL) was added t-BuONa (68.1 mg,708 umol, 2.0 eq). The mixture was stirred at 0° C. for 0.5 hour. Aftercompletion, the mixture was added water (10.0 mL) and extracted withethyl acetate (10.0 mL×3). The organic layer was dried over Na₂SO₄,filtered and concentrated. The residue was purified by reversed phaseflash column (C18, 0.1% FA in water, 0-40% MeCN). The product tert-butyl2-(cyanomethyl)-4-[2-[2-(diethylamino)ethoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(180 mg, 291 umol, 82.3% yield) was obtained as a colorless oil. LCMS[ESI, M+1]: 618.

Step B: 2-(4-(2-(2-(diethylamino)ethoxy)-7-(2-(trifluoromethylphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.To a solution of tert-butyl2-(cyanomethyl)-4-(2-(2-(diethylamino)ethoxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(180 mg, 291 umol, 1.0 eq) in DCM (2.0 mL) was added TFA (33.2 mg, 291umol, 21.6 uL, 1.0 eq). The mixture was stirred at 25° C. for 0.5 hour.After completion, the reaction mixture was added ethyl acetate (10.0mL,) and adjusted with saturated NaHCO₃ solution to pH>7. The mixturewas extracted with ethyl acetate (30 ml-3) and the organic layer wasdried with Na₂SO₄ and filtered. The solvent was removed under vacuum.The product2-(4-(2-(2-(diethylamino)ethoxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(150 mg, crude) was obtained as yellow oil. LCMS [ESI, M+1]: 518.

Step C:2-[4-[2-[2-(diethylamino)ethoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[4-[2-[2-(diethylamino)ethoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(150 mg, crude) in DCM (3.0 mL) was added DIEA (129 mg, 1.0 mmol, 174uL) and prop-2-enoyl prop-2-enoate (44.1 mg, 0.35 mmol). The mixture wasstirred at 0° C. for 1 hour. After completion, the reaction mixture wasquenched by addition methanol (10.0 mL) at 20° C. To the reactionmixture, water (10.0 mL) was added, and extracted with DCM (10.0 mL×3).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under vacuum to give a residue. The residue was purified byprep-HPLC (column: Gemini 150*25 5 u; mobile phase: [water (0.04%NH3H2O)-ACN]; B %: 65%-83%, 10 min). The product2-[4-[2-[2-(diethylamino)ethoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 300, 41.6 mg, 72.7 umol, 100% purity, two steps yield 25.0%)was obtained as a white solid. LCMS [ESI, M+1]: 572.

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.68 (d, J=7.8 Hz, 1H), 7.58 (t, J=7.4Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.32-7.28 (m, 1H), 6.70-6.49 (m, 1H),6.39 (dd, J=1.2, 16.8 Hz, 1H), 5.82 (d, J=10.8 Hz, 1H), 5.08 (br, s,1H), 4.39 (t, J=6.8 Hz, 2H), 4.14-4.00 (m, 3H), 4.02-3.84 (m, 1H), 3.32(br d, J=12.0 Hz, 1H), 3.24-3.16 (m, 1H), 3.15-3.04 (m, 2H), 2.96-2.88(m, 4H), 2.87-2.70 (m, 1H), 2.68-2.61 (m, 4H), 1.89 (br s, 3H), 1.07 (t,J=7.0 Hz, 6H).

Example 301

2-[4-[7-(1-naphthyl)-2-[[(2S)-1,5,5-trimethylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: tert-butyl(5S)-5-(hydroxymethyl)-2,2-dimethyl-pyrrolidine-1-carboxylate. To asolution of(2S)-1-tert-butoxycarbonyl-5,5-dimethyl-pyrrolidine-2-carboxylic acid(400 mg, 1.64 mmol, 1.00 eq) in anhydrous THF (7.00 m L) was addedBH₃Me₂S (10 M, 493 uL, 3.00 eq) dropwise at 25° C. The reaction washeated at 50° C. for 5 minutes. Upon completion, after cooled by anice-bath, the mixture was quenched with Methanol (10 mL). The reactionmixture was concentrated under reduced pressure to give tert-butyl(5S)-5-(hydroxymethyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (360 mg,1.57 mmol, 95.9%) as a colorless oil which was used directly into thenext step without further purification.

Step B: tert-butyl4-[3-(cyanomethyl)piperazin-1-yl]-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate.To a stirred solution of tert-butyl2-methylsulfanyl-4-(trifluoromethylsulfonyloxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(20 g, 46.5 mmol, 1.00 eq) in DMF (300 mL) was added DIEA (18.1 g, 139mmol, 24.3 mL, 3 eq) and 2-piperazin-2-ylacetonitrile (10.2 g, 51.2mmol, 495 uL, 1.10 eq, 2 HCl). The reaction was heated to 100° C. andstirred for 1 hour under N₂ atmosphere. tert-butyl4-[3-(cyanomethyl)piperazin-1-yl]-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(18.8 g, crude) was obtained and used to next step directly withoutwork-up and purification.

Step C: tert-butyl4-[4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate.To a solution of tert-butyl4-[3-(cyanomethyl)piperazin-1-yl]-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(18.8 g, crude) in DMF (200 mL) was added DIEA (12.0 g, 92.9 mmol, 16.2mL) and benzyl carbonochloridate (11.9 g, 69.7 mmol, 9.91 mL). Themixture was stirred at 50° C. for 1 hour. The reaction mixture wasdiluted with water (300 mL) and extracted with ethyl acetate (200 mL×3).The combined organic layers were washed with brine (200 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=30/1 to 3/1). tert-butyl4-[4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(20 g, 31.6 mmol, two steps 68.0% yield, 85% purity) was obtained as ayellow oil. LCMS [ESI, M+1]: 539.

¹H NMR (400 MHz, chloroform-d) δ=7.40-7.36 (m, 5H), 5.21-5.15 (m, 2H),4.73-4.55 (m, 2H), 4.39 (d, J=18.8 Hz, 1H), 3.97 (d, J=12.8 Hz, 1H),3.90-3.69 (m, 2H), 3.41-3.16 (m, 3H), 3.00 (dt, J=3.6, 12.4 Hz, 1H),2.86-2.53 (m, 5H), 2.51 (s, 3H) 1.49 (s, 9H).

Step D: benzyl2-(cyanomethyl)-4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate.To a solution of tert-butyl 4-[4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(11 g, 20.4 mmol, 1.00 eq) in dioxane (100 mL) was added HCl·dioxane (4M, 102 mL, 20 eq). After stirred at 25° C. for 1 hour, the reactionmixture was concentrated under reduced pressure to give a residue. Theresidue was dissolved in 300 mL of ethyl acetate and 300 mL of water andstirred rapidly. Then saturated Na₂CO₃ aqueous solution was added untilthe pH˜9. The organics was washed with water (1×300 mL) and brine (1×200mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure. benzyl2-(cyanomethyl)-4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(8.2 g, 15.2 mmol, 74.2% yield, 81% purity) was obtained as a yellow oiland used to next step directly without purification. LCMS [ESI, M+1]:439.

Step E: Benzyl2-(cyanomethyl)-4-[2-methylsulfanyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.A mixture of benzyl2-(cyanomethyl)-4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(5.07 g, 11.6 mmol, 1.1 eq), 1-bromonaphthalene (2.83 g, 13.7 mmol, 1.90mL, 1.3 eq), Cs₂CO₃ (8.57 g, 26.3 mmol, 2.50 eq), Pd₂(dba)₃ (1.45 g,1.58 mmol, 0.15 eq) and RuPhos (982 mg, 2.11 mmol, 0.20 eq) in dioxane(100 mL) was degassed and purged with N₂ for 3 times, and then themixture was stirred at 85° C. for 5 hours under N₂ atmosphere. Thereaction mixture was diluted with water (200 mL) and extracted withethyl acetate (200 mL×3). The combined organic layers were washed withbrine (200 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 2/1).Benzyl2-(cyanomethyl)-4-[2-methylsulfanyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(3.6 g, 4.65 mmol, 40.1% yield, 73% purity) was obtained as a yellowoil. LCMS [ESI, M+1]: 565.

Step F: benzyl2-(cyanomethyl-4-[2-methylsulfinyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a stirred solution of benzyl2-(cyanomethyl)-4-[2-methylsulfanyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(3.1 g, 5.49 mmol, 1 eq) in methyltetrahydrofuran (50 mL) at 0° C. undernitrogen was added m-CPBA (1.18 g, 5.49 mmol, 80% purity, 1 eq) neat asa solid. After stirred at 0° C. for 1 hour under Ni atmosphere, thereaction mixture was quenched by addition 10% of Na₂S₂O₃ (100 mL)aqueous solution at 0° C., and then diluted with water (200 mL) andextracted with ethyl acetate (200 mL). The combined organic layers werewashed with brine (200 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give a residue. The residue was purified bycolumn chromatography (SiO₂, Ethyl acetate/Methanol=100/1 to 10/1) andfurther purified by reversed phase flash [water (0.1% formicacid)/acetonitrile)]. The desired fractions were adjusted pH=7 byaddition saturated NaHCO₁ aqueous solution and extracted with ethylacetate (100 mL×3). The combined organic layers were washed with brine(50 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give benzyl2-(cyanomethyl)-4-[2-methylsulfinyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1.3 g, 2.19 mmol, 39.9% yield, 98% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 581.

¹H NMR (400 MHz, chloroform-d) δ=8.22-8.13 (m, 1H), 7.92-7.83 (m, 1H),7.63 (d, J=80 Hz, 1H), 7.56-7.48 (m, 2H), 7.45 (t, J=8.0 Hz, 1H),7.41-7.32 (m, 5H), 7.15 (d, J=7.2 Hz, 1H), 5.22 (s, 2H), 4.70 (br s,1H), 4.54-4.36 (m, 2H), 4.34-4.17 (m, 2H), 4.12-4.04 (m, 1H), 3.58-3.17(m, 5H), 3.01 (m, 2H), 2.93 (d, J=2.8 Hz, 3H), 2.90-2.79 (m, 1H),2.77-2.65 (m, 1H).

Step G: To a solution of benzyl2-(cyanomethyl)-4-[2-methylsulfinyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(430 mg, 741 umol, 1.00 eq) and tert-butyl(5S)-5-(hydroxymethyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (340 mg,1.48 mmol, 2.00 eq) in toluene (8.00 mL) was added t-BuONa (142 mg, 1.48mmol, 2.00 eq). The mixture was stirred at 20° C. for 0.25 hour. Uponcompletion, the reaction mixture was filtered and the filtrate wasconcentrated. The residue was purified by reversed-phase flash [water(0.1% FA)/acetonitrile] to give benzyl4-[2-[[(2S)-1-tert-butoxycarbonyl-5,5-dimethyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(250 mg, 318 umol, 43.0% yield, 95.0% purity) as a yellow solid. LCMS[ESI, M+1]: 746.

Step H: benzyl2-(cyanomethyl)-4-[2-[[(2S)-5,5-dimethylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of benzyl4-[2-[[(2S)-1-tert-butoxycarbonyl-5,5-dimethyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(200 mg, 268 umol, 1.00 eq) in dioxane (4.00 mL) was added HCl·dioxane(4 M, 4.00 mL, 59.7 eq) at 0° C. The mixture was stirred at 25° C. for 2hours. Upon completion, the mixture was concentrated under vacuum togive benzyl2-(cyanomethyl)-4-[2-[[(2S)-5,5-dimethylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(180 mg, 251 umol, 93.5% yield, 95.0% purity, HCl) as a yellow oil whichwas used directly into the next step without further purification.

Step I: benzyl2-(cyanomethyl)-4-[7-(1-naphthyl)-2-[[(2S)-1,5,5-trimethylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of benzyl2-(cyanomethyl)-4-[2-[[(2S)-5,5-dimethylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(180 mg, 264 umol, 1.00 eq, HCl) and formaldehyde (107 mg, 1.32 mmol,98.2 uL, 5.00 eq, 37% in water) in MeOH (3.00 mL) was added CH₃COOH(31.7 mg, 528 umol, 30.2 uL, 2.00 eq) and NaBH₃CN (66.3 mg, 1.06 mmol,4.00 eq). The mixture was stirred at 25° C. for 1 hour. Upon completion,the mixture was quenched with 1 M HCl (0.2 mL), diluted with water (1mL) and extracted with EtOAc (3×6 mL). The organic layers were driedover Na₂SO₄ and concentrated under vacuum. The residue was purified byreversed-phase flash [water (0.1% FA)/acetonitrile] to give benzyl2-(cyanomethyl)-4-[7-(1-naphthyl)-2-[[(2S)-1,5,5-trimethylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(96.0 mg, 131 umol, 49.6% yield, 90.0% purity) as a yellow solid.

¹H NMR (400 MHz, chloroform-d) δ=8.23-8.17 (m, 1H), 7.89-7.83 (m, 1H),7.61 (d, J=8.0 Hz, 1H), 7.53-7.47 (m, 2H), 7.46-7.42 (m, 1H), 7.42-7.33(m, 5H), 7.14 (d, J=7.2 Hz, 1H), 5.27-5.16 (m, 2H), 4.70 (br s, 1H),4.41 (dd, J=4.4, 10.4 Hz, 1H), 4.34-4.22 (m, 2H), 4.20-4.01 (m, 3H),3.95 (br d, J=11.2 Hz, 1H), 3.40-3.21 (m, 3H), 3.13-2.91 (m, 2H),2.91-2.69 (m, 3H), 2.32 (s, 3H), 2.13-1.96 (m, 1H), 1.75-1.54 (m, 5H),1.15 (s, 3H), 0.92 (s, 3H).

Step J:2-[4-[7-(1-naphthyl)-2-[[(2S)-1,5,5-trimethylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.NH₃ was bubbled into MeOH (6.00 mL) for 3 minutes at −40° C. A solutionof benzyl2-(cyanomethyl)-4-[7-(1-naphthyl)-2-[[(2S)-1,5,5-trimethylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.10 g 152 umol, 1.00 eq) in MeOH (6.00 mL) was added to the NH₃solution and Pd/C (0.05 g, 10% purity) under N₂. The suspension wasdegassed under vacuum and purged with H₂ several times. The reaction wasstirred under H₂ (15 psi) at 25° C. for 1 hour. Upon completion, thecatalyst was filtered off and the filtrate was concentrated under vacuumto give2-[4-[7-(1-naphthyl)-2-[[(2S)-1,5,5-trimethylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(63.0 mg, 103 umol, 68.0% yield, 86.0% purity) as a yellow solid whichwas used directly into the next step without further purification. LCMS[ESI, M+1]: 526.

Step K:2-[4-[7-(1-naphthyl)-2-[[(2S)-1,5,5-trimethylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of 2-[4-[7-(1-naphthyl)-2-[[(2S)-1,5,5-trimethylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(75.0 mg, 143 umol, 1.00 eq) and TEA (72.2 mg, 713 umol, 99.3 uL, 5.00eq) in DCM (2.00 mL) was added prop-2-enoyl prop-2-enoate (18.0 mg, 143umol, 1.00 eq) dropwise at 0° C. The mixture was stirred at 25° C. for 1hour. Upon completion, the reaction was quenched with MeOH (0.5 mL),diluted with water (2 mL) and extracted with EtOAc (2×5 mL). The organiclayers were dried over Na₂SO₄, filtered and concentrated under vacuum.The residue was purified by prep-TLC (EtOAC/MeOH 9/1) and prep-HPLC(column: Phenomenex Gemini 150*25 mm*10 um; mobile phase: [water (0.05%ammonia hydroxide v/v)-ACN]; B %: 60%-90%, 12 min) and lyophilized togive2-[4-[7-(1-naphthyl)-2-[[(2S)-1,5,5-trimethylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 301, 14.7 mg, 25.3 umol, 17.8% yield, 100% purity) as a whitesolid. LCMS [ESI, M+1]: 580.

¹H NMR (400 MHz, chloroform-d) δ=8.25-8.17 (m, 1H), 7.90-7.83 (m, 1H),7.61 (d, J=8.4 Hz, 1H), 7.55-7.48 (m, 2H), 7.44 (t, J=7.6 Hz, 1H), 7.14(d, J=7.2 Hz, 1H), 6.60 (br s, 1H), 6.45-6.36 (m, 1H), 5.84 (br d,J=10.8 Hz, 1H), 5.10 (br s, 1H), 4.44 (br s, 1H), 4.34-4.19 (m, 2H),4.17-3.80 (m, 4H), 3.79-3.21 (m, 4H), 3.19-2.63 (m, 6H), 2.34 (br s,3H), 2.15-2.03 (m, 1H), 1.69 (br s, 3H), 1.16 (br s, 3H), 0.94 (s, 3H).

Example 302

2-[4-[7-(7-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-2-piperidyl]acetonitrile

Insert: (7-fluoro-1-naphthyl) trifluoromethanesulfonate. To a solutionof 7-fluoronaphthalen-1-ol (250 mg, 1.54 mmol, 1 eq) and DIEA (598 mg,4.63 mmol, 806 uL, 3 eq) in DCM (10 mL) was added Tf₂O (652 mg, 2.31mmol, 382 uL, 1.5 eq) dropwise at −5° C. The mixture was stirred at 20°C. for 3 hours. After that, the mixture was concentrated under vacuum.The residue was purified by silica gel chromatography (Petroleumether/Ethyl acetate=100/1 to 10/1). (7-fluoro-1-naphthyl)trifluoromethanesulfonate (450 mg, 1.53 mmol, 99.2% yield) was obtainedas a colourless oil.

¹H NMR (400 MHz, methanol-d₄) δ=8.08 (dd, J=5.6, 9.2 Hz, 1H), 8.01 (d,J=8.4 Hz, 1H), 7.73-7.39 (m, 4H).

Step A: tert-Butyl2-(cyanomethyl)-4-[7-(7-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a mixture of tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(182 mg, 386 umol, 1 eq), (7-fluoro-1-naphthyl)trifluoromethanesulfonate (227 mg, 772 umol, 2 eq), Pd₂(dba)₃ (35.3 mg,38.6 umol, 0.1 eq), RuPhos (36.0 mg, 77.2 umol, 0.2 eq) and Cs₂CO₃ (377mg, 1.16 mmol, 3 eq) in toluene (20 mL) was degassed and purged with N₂for 3 times, and then the mixture was stirred at 90° C. for 16 hoursunder N₂ atmosphere. The mixture was quenched with H₂O (30 mL), and thenthe mixture was diluted with ethyl acetate (20 mL). The separatedorganic layer was dried over sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by reversed phase flash [water(0.1% FA)/acetonitrile]. The desired fractions were collected andneutralized with saturated NaHCO₃ solution and extracted with ethylacetate (1×100 mL). The organic layer was dried over sodium sulfate,filtered and concentrated under vacuum. tert-Butyl2-(cyanomethyl)-4-[7-(7-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(158 mg, 257 umol, 66.5% yield, 100% purity) was obtained as a yellowoil. LCMS [ESI, M+1]: 616.

¹H NMR (400 MHz, chloroform-d) δ=7.92-7.79 (m, 2H), 7.61 (d, J=8.0 Hz,1H), 7.40 (t, J=7.8 Hz, 1H), 7.30-7.25 (m, 1H), 7.19 (d, J=7.2 Hz, 1H),4.63 (br d, J=2.1 Hz, 1H), 4.40 (br dd, J=4.8, 10.4 Hz, 1H), 4.24 (br s,2H), 4.20-4.00 (m, 4H), 3.95 (br d, J=12.4 Hz, 1H), 3.52-3.37 (m, 1H),3.36-3.16 (m, 3H), 3.15-2.63 (m, 6H), 2.50 (s, 3H), 2.36-2.22 (m, 1H),2.12-2.05 (m, 1H), 1.92-1.70 (m, 3H), 1.53 (s, 9H).

Step B:2-[4-[7-(7-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5N-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl2-(cyanomethyl)-4-[7-(7-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(100 mg, 162 umol, 1 eq) in dioxane (10 mL) was added HCl·dioxane (4 M,1.62 mL, 40 eq) at 0° C. under nitrogen atmosphere. The mixture wasstirred at 25° C. for 2 hours. After that, the mixture was concentratedunder vacuum.2-[4-[7-(7-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(100 mg, crude, HCl) was obtained as a yellow oil. LCMS [ESI, M+1]: 516.

Step C:2-[4-[7-(7-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-2-piperidyl]acetonitrile.To a mixture of2-[4-[7-(7-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(100 mg, crude, HCl) and DIEA (234 mg, 1.81 mmol, 315 uL) in DMF (5 mL)was added prop-2-enoyl prop-2-enoate (18.3 mg, 145 umol) at 0° C. Afterstirred at 25° C. for 1 h, the reaction mixture was quenched by NaHCO₃saturated solution (5 mL), and then extracted with ethyl acetate (2×25mL). The combined organic layers were washed with brine (1×50 mL), driedover sodium sulfate, filtered and concentrated under vacuum. The residuewas purified by silica gel chromatography (Ethyl acetate/MeOH=50/1 to1/1). The collected liquid was concentrated under vacuum. The residuewas purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um;mobile phase: [water (0.225% FA)-ACN]; B %: 12%-42%, 10 min) and(column: Phenomenex Gemini 150*25 mm*10 um; mobile phase: [water (0.05%,ammonia hydroxide v/v)-ACN]; B %: 55%-85%, 12 min)2-[4-[7-(7-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-2-piperidyl]acetonitrile(EXAMPLE 302, 4.23 mg, 7.19 umol, two steps 4.29% yield, 96.7% purity)was obtained as a white solid. LCMS [ESI, M+1]: 570.

¹H NMR (400 MHz, chloroform-d) δ=7.93-7.77 (m, 2H), 7.61 (d, J=8.0 Hz,1H), 7.40 (t, J=7.8 Hz, 1H), 7.32-7.25 (m, 1H), 7.19 (d, J=7.3 Hz, 1H),6.59 (br d, J=10.8 Hz, 1H), 6.41 (dd, J=1.6, 16.8 Hz, 1H), 5.84 (br d,J=10.4 Hz, 1H), 5.23-4.52 (m, 1H), 4.40 (dd, J=4.8, 10.6 Hz, 1H), 4.24(br s, 2H), 4.21-4.11 (m, 2H), 4.03 (br d, J=12.0 Hz, 2H), 3.86-3.04 (m,6H), 3.03-2.58 (m, 5H), 2.49 (s, 3H), 2.37-2.23 (m, 1H), 2.16-1.98 (m,1H), 1.91-1.69 (m, 3H).

Example 303

2-[4-[7-(1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: benzyl(2S)-2-(cyanomethyl)-4-[7-(1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of 2-(1-piperidyl)ethanol (89.0 mg, 689 umol, 91.5 uL, 2.0eq) in toluene (2.0 mL) was added t-BuONa (66.2 mg, 689 umol, 2.0 eq) at0° C. Then the mixture was added benzyl(2)-2-(cyanomethyl)-4-[2-methylsulfinyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 344 umol, 1.0 eq), the mixture was stirred at 0° C. for 1 hour.After completion, the mixture was added water (10.0 mL) and extractedwith EA (10 mL×3). The organic layer was dried over Na₂SO₄, filtered andconcentrated. The obtained product was purified by column chromatography(SiO₂, PE:EA=10:1-EA:MeOH=20:1) to give benzyl(2S)-2-(cyanomethyl)-4-[7-(1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 296 umol, 86% yield, 95.7% purity) as yellow oil. LCMS [ESI,M+1]: 646.

Step B:2-[(2S)-4-[7-(1-naphthyl-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.NH₃ was bubbled into MeOH (10.0 mL) at −78° C. for 30 minutes. Thenbenzyl(2S)-2-(cyanomethyl)-4-[7-(1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(180 mg, 279 umol, 1.0 eq) and Pd/C (100 mg, 10.0% purity) was added tothe above liquid under N₂ atmosphere. The suspension was degassed andpurged with H₂ for 3 times. The mixture was stirred under H₂ (15 Psi) at20° C. for 0.5 hour. After completion, the mixture was filtered withCelite and concentrated under vacuum. The obtained product was purifiedby reversed phase flash column (C18, 0.1% FA in water, 0-40% MeCN) togive2-[(2S)-4-[7-(1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(90.0 mg, 176 umol, 63% yield) as white solid. LCMS [ESI, M+1]: 512.

Step C:2-[4-[7-(1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of 2-[4-[7-(1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(90.0 mg, 176 umol, 1.0 eq) and DIEA (136 mg, 1.06 mmol, 184 uL, 6.0 eq)in DCM (1.0 mL) was added prop-2-enoyl prop-2-enoate (22.2 mg, 176 umol,1.0 eq). The mixture was stirred at 0° C. for 0.5 hour. Aftercompletion, the mixture was quenched with MeOH (20.0 mg) andconcentrated under vacuum. The obtained product was purified byprep-HPLC (column: Phenomenex Gemini 150*25 mm*10 um; mobile phase:[water (0.05% ammonia hydroxide v/v)-ACN]; B %: 60%-90%, 12 min) to give2-[4-[7-(1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 303, 11.2 mg, 19.7 umol, 11% yield, 99.5% purity) as whitesolid. LCMS [ESI, M+1]: 566.

¹H NMR (400 MHz, Chloroform-d) δ 8.24-8.19 (m, 1H), 7.89-7.84 (m, 1H),7.62 (d, J=8.4 Hz, 1H), 7.55-7.47 (m, 2H), 7.44 (t, J==8.0 Hz, 1H), 7.15(d, J==7.6 Hz, 1H), 6.70-6.53 (m, 1H), 6.41 (dd, J=1.2, 16.8 Hz, 1H),5.84 (br d, J=10.4 Hz, 1H), 5.19-5.01 (m, 1H), 4.47 (br t, J=6.0 Hz,2H), 4.33-4.21 (m, 2H), 4.12 (br d, J=14.0 Hz, 1H), 4.06-3.98 (m, 1H),3.55-3.45 (m, 1H), 3.43-3.24 (m, 2H), 3.22-3.09 (m, 1H), 3.04-2.72 (m,6H), 2.68-2.42 (m, 4H), 1.61-1.56 (m, 6H), 1.50-1.40 (m, 2H).

Example 304

2-[4-[2-[[(2R)-1-(2-hydroxyethyl)pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

[(2R)-1-[2-[tert(dimethyl) silyl]oxyethyl]pyrrolidin-2-yl] methanol. Amixture of [(2R)-pyrrolidin-2-yl]methanol (0.70 g 6.92 mmol, 673 uL,1.00 eq), 2-bromoethoxy-tert-butyl-dimethyl-silane (1.66 g, 6.92 mmol,1.00 eq) and K₂CO₃ (4.78 g, 34.6 mmol, 5.00 eq) in acetonitrile (70.0mL) was refluxed at 83° C. for 12 hours. Then the mixture was filteredand the filter cake was washed with methanol. The organic layers wereconcentrated under vacuum to give a residue. The residue was purified bysilica gel chromatography (ethyl acetate/methanol=50/1 to 1/1). Compound[(2R)-1-[2-[tert-butyl(dimethyl) silyl]oxyethyl]pyrrolidin-2-yl]methanol(1.40 g, 5.40 mmol, 78.0% yield, 100% purity) was obtained as acolorless oil.

¹H NMR (400 MHz, chloroform-d) δ=3.68 (dd, J=5.2, 6.4 Hz, 2H), 3.57 (dd,J=3.6, 10.8 Hz, 1H), 3.42-3.25 (m, 1H) 3.23-2.96 (m, 2H), 2.95-2.82 (m,1H), 2.72-2.61 (m, 1H), 2.48 (td, J=5.2, 12.8 Hz, 1H), 2.40-2.27 (m,1H), 1.90-1.77 (m, 1H), 1.77-1.62 (m, 3H), 0.83 (s, 9H), 0.00 (s, 6H).

Step A: benzyl4-[2-[[(2R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.To a solution of benzyl2-(cyanomethyl)-4-[2-methylsulfinyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 861 umol, 1 eq) and[(2R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-yl]methanol(447 mg, 1.72 mmol, 2 eq) in toluene (10 mL) was added t-BuONa (248 mg,2.58 mmol, 3 eq) in one portion at 25° C. and the mixture was stirred at25° C. for 0.5 hour. The mixture was acidified with 1 M HCl solution topH 8 and the mixture diluted with ethyl acetate (100 mL) and water (10mL). The separated organic layer was washed with brine (1×50 mL), driedover sodium sulfate, filtered and concentrated under vacuum. The residuewas purified by column chromatography over silica gel (ethylacetate/methanol 100/1 to 10/1). The desired fractions were collectedand concentrated under vacuum to give benzyl4-[2-[[(2R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(480 mg, 582 umol, 68% yield, 94.1% purity) as a light yellow solid.LCMS [ESI, M+1]: 776.

¹H NMR (400 MHz, chloroform-d) δ=8.28-8.11 (m, 1H), 7.95-7.77 (m, 1H),7.61 (d, J=8.0 Hz, 1H), 7.55-7.29 (m, 8H), 7.14 (d, J=7.2 Hz, 1H),5.29-5.15 (m, 2H), 4.70 (br s, 1H), 4.41-3.88 (m, 7H), 3.83-3.68 (m,2H), 3.57-2.69 (m, 12H), 2.67-2.49 (m, 1H), 2.37 (q, J=8.4 Hz, 1H),2.03-1.93 (m, 1H), 1.83-1.74 (m, 3H), 1.00-0.79 (m, 9H), 0.13-0.01 (m,6H).

Step B: 2-[4-[2-[[(2R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.NH₃ was bubbled in methanol (60.0 mL) at −78° C. for 30 minutes. Benzyl4-[2-[[(2R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(0.20 g, 258 umol, 1.00 eq) and Pd/C (0.10 g, 10.0% purity) was addedinto the mixture. The mixture was stirred at 20° C. for 1 hour under H₂at 15 psi. Then the mixture was filtered and concentrated under vacuumto give 2-[4-[2-[[(2R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(0.15 g, crude) as a yellow oil and used into next step without furtherpurification. LCMS [ESI, M+1]: 642.

Step C: 2-[4[2-[[(2R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[4-[2-[[(2R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(0.15 g, crude) and Et₃N (236 mg, 2.34 mmol, 325 uL) in dichloromethane(2.00 mL) was added prop-2-enoyl prop-2-enoate (29.5 mg, 234 umol) at 0°C. After stirred at 20° C. for 1 hour, the mixture was quenched withsaturated sodium bicarbonate solution (0.50 mL) and concentrated undervacuum. The residue was purified by column chromatography (Al₂O₃,methanol/ethyl acetate=1/10) to give2-[4-[2-[[(2R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(0.10 g, 135 umol, two steps 52.3% yield) as a yellow solid. LCMS [ESI,M+1]: 696.

¹H NMR (400 MHz, chloroform-d) δ=8.25-8.18 (m, 1H), 7.90-7.82 (m, 1H),7.61 (d, J=8.0 Hz, 1H), 7.54-7.47 (m, 2H), 7.43 (t, J=7.6 Hz, 1H), 7.15(d, J=7.2 Hz, 1H), 6.59 (br d, J=12.0 Hz, 1H), 6.40 (dd, J=1.2, 16.8 Hz,1H), 5.84 (br d, J=10.4 Hz, 1H), 5.22-4.94 (m, 1H), 4.36 (td, J=3.6,10.4 Hz, 1H), 4.31-4.20 (m, 2H), 4.15-4.05 (m, 2H), 4.04-3.97 (m, 1H),3.75 (t, J=6.8 Hz, 2H), 3.63 (br s, 1H), 3.46 (br s, 1H), 3.35 (br d,J=11.2 Hz, 2H), 3.21-3.15 (m, 1H), 3.08-2.99 (m, 2H), 2.99-2.92 (m, 2H),2.63-2.54 (m, 1H), 2.42-2.33 (m, 1H), 2.04-1.95 (m, 1H), 1.84-1.73 (m,3H), 1.66 (br s, 4H), 0.88 (s, 9H), 0.05 (s, 6H).

Step D:2-[4-[2-[[(2R)-1-(2-hydroxyethyl)pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.A mixture of 2-[4-[2-[[(2R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-yl)pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(0.09 g, 129 umol, 1 eq) and TBAF (1.00 M in THF, 1.29 mL, 10 eq) in THF(0.10 mL) was stirred at 10° C. for 1 hour. The mixture was concentratedunder vacuum. The residue was purified by reverse phase flash [water(FA, 0.1%)/acetonitrile], column chromatography (Al₂O₃, methanol/ethylacetate=1/3) and prep-HPLC (column: Boston pH-lex 150*25 10 um; mobilephase (water (0.10% TFA)-ACN]; B %: 22%-52%, 10 min and column:Phenomenex Gemini 150*25 mm*10 um; mobile phase: [water (0.05% ammoniahydroxide v/v)-ACN]; B %: 47%-77%, 12 min). The desired fractions werecollected and lyophilized to give title compound2-[4-[2-[[(2R)-1-(2-hydroxyethyl)pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(23.9 mg, 41.0 umol, 31.7% yield, 99.7% purity) as a white solid LCMS[ESI, M+1]: 582.

¹H NMR (400 MHz, chloroform-d) δ=8.25-8.18 (m, 1H), 7.89-7.83 (m, 1H),7.61 (d, J=8.4 Hz, 1H), 7.54-7.47 (m, 2H), 7.43 (t, J=7.6 Hz, 1H), 7.14(d, J=7.2 Hz, 1H), 6.59 (br s, 1H), 6.44-6.35 (m, 1H), 5.83 (br d,J=10.4 Hz, 1H), 5.10-4.50 (m, 1H), 4.38-4.24 (m, 3H) 4.22-4.09 (m, 2H),4.00 (br d, J=11.5 Hz, 2H), 3.73-3.57 (m, 2H), 3.45 (br s, 1H), 3.36 (brd, J=12.0 Hz, 2H), 3.23-2.77 (m, 9H), 2.62 (td, J=3.6, 12.4 Hz, 1H),2.38-2.26 (m, 1H), 2.05-1.99 (m, 1H), 1.90-1.73 (m, 3H).

Example 305

3-(4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)isonicotinonitrile

Step A: benzyl2-(cyanomethyl)-4-[7-(4-cyano-3-pyridyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of benzyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(400 mg, 791 umol, 1.0 eq) and 3-bromopyridine-4-carbonitrile (289 mg,1.58 mmol, 2.0 eq) in toluene (10.0 mL) was added Cs₂CO₃ (516 mg, 1.58mmol, 2.0 eq), Pd₂(dba)₃ (72.4 mg, 79.1 umol, 0.1 eq) and RuPhos (73.8mg, 158 umol, 0.2 eq), the reaction mixture was stirred at 100° C. for 3hours under N₂. After completion, the reaction mixture was added water(15 mL), then extracted with EA (2×15.0 mL), the combined organic layerwas dried over NaSO₄, filtered and concentrated. The residue waspurified by column chromatography (Base Al₂O₃, Petroleum ether/Ethylacetate=5/1 to Petroleum ether/Ethyl acetate/Methanol=5/1/0.1) to givebenzyl2-(cyanomethyl)-4-[7-(4-cyano-3-pyridyl)-2-[[(2S)-1-methylpyrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 266 umol, 34% yield, 80.9% purity) as yellow solid. LCMS [ESI,M+1]: 608.

Step B: 3-[4-[3-(cyanomethyl)piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]pyridine-4-carbonitrile.To a solution of benzyl2-(cyanomethyl)-4-[7-(4-cyano-3-pyridyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(170 mg, 226 umol, 1.0 eq) in MeOH (5.0 mL) was added NH₃·MeOH (49.4 ug,49.4 umol, 5.0 mL) and Pd/C (150 mg, 10% purity), the suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred under H₂ (15 Psi) at 20° C. for 1 hour. After completion, thereaction was filtered through a Celite, and the filtrate wasconcentrated. The residue was purified by reversed phase flash (C18, 30%MeCN in water), the obtained product was adjusted with saturated NaHCO₃aqueous to pH˜8, then concentrated until no solvent remained, the solidwas then added DCM (10.0 mL) and stirred at 20° C. for 0.5 h, the solidwas filtered and the filtrate was concentrated to give3-[4-[3-(cyanomethyl)piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]pyridine-4-carbonitrile(35.0 mg, 73.9 umol, 33% yield, 100% purity) as white solid. LCMS [ESI,M+1]: 474.

Step C:3-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]pyridine-4-carbonitrile.To a mixture of3-[4-[3-(cyanomethyl)piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]pyridine-4-carbonitrile(35.0 mg, 73.9 umol, 1.0 eq) in DCM (1.0 mL) was added DIEA (28.7 mg,222 umol, 38.6 uL, 3.0 eq) and prop-2-enoyl prop-2-enoate (9.32 mg, 73.9umol, 1.0 eq) at 0′C, the reaction mixture was stirred at 20° C. for 0.5hour. After completion, the reaction mixture was quenched with MeOH (0.5mL), and concentrated. The residue was purified by prep-HPLC((Instrument: ACSWH-GX-M; Column: Gemini 150*25 5 u; Condition: water(0.04% NH₃·H₂O)-ACN; Begin B: 32; End B: 56; Gradient Time (min): 10;100% B Hold Time (min): 3; FlowRate (ml/min): 100), the obtained productwas concentrated, and then under lyophilization. The product3-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]pyridine-4-carbonitrile(EXAMPLE 305, 13.0 mg, 24.5 umol, 33% yield, 99.3% purity) was obtainedas yellow solid. LCMS [ESI, M+1]: 528.

¹H NMR (400 MHz, chloroform-d) δ 8.52 (s, 1H), 8.33 (d, J=4.8 Hz, 1H),7.46 (d, J=4.8 Hz, 1H), 6.69-6.53 (m, 1H), 6.42 (dd, J=1.6, 16.8 Hz,1H), 5.85 (br d, J=11.6 Hz, 1H), 5.19-5.01 (m, 1H), 4.48-4.36 (m, 3H),4.27-4.08 (m, 2H), 4.07-3.81 (m, 3H), 3.78-3.33 (m, 3H), 3.23-2.99 (m,3H), 2.97-2.83 (m, 2H), 2.81-2.61 (m, 2H), 2.52 (s, 3H), 2.40-2.27 (m,1H), 2.16-1.99 (m, 1H), 1.95-1.76 (m, 3H).

Example 306

2-((S)-1-acryloyl-4-(2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: [(2S,4R)-4-fluoro-1-methyl-pyrolidin-2-yl] methanol. To asolution of 1-tert-butyl 2-methyl(2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylate (5.0 g, 20.2 mmol, 1.0 eq)in THF (100 mL) was added LiAlH₄ (1.53 g, 40.4 mmol, 2.0 eq) in portionsat 0° C. After the reaction mixture was stirred at 0° C. for 1 hourunder N₂, the reaction mixture was heated to 70° C. and stirred at 70°C. for 2 hours under N₂. After completion, the reaction mixture wasquenched with saturated Na₂SO₄ aqueous (4.5 mL), then filtered, thefiltrate was concentrated. The residue was purified by columnchromatography (Base Al₂O₃, Petroleum ether/Ethyl acetate=5/1 toPetroleum ether/Ethyl acetate/Methanol=3/1/0.1) to give[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl] methanol (1.5 g, 11.3 mmol,56% yield) as yellow oil.

¹H NMR (400 MHz, chloroform-d) δ 5.24-4.97 (m, 1H), 3.73 (dd, J=3.2,11.2 Hz, 1H), 3.61-3.40 (m, 2H), 2.86-2.74 (m, 1H), 2.69 (ddd, J=0.8,2.8, 12.0 Hz, 1H), 2.61 (dd, J=2.4, 12.0 Hz, 1H), 2.41 (s, 3H),2.18-1.98 (m, 2H).

Step B: benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[2-methylsulfinyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(Intermediate 64, 800 mg, 1.38 mmol, 1.0 eq) and[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methanol (367 mg, 2.76 mmol,2.0 eq) in toluene (15.0 mL) was added t-BuONa (265 mg, 2.76 mmol, 2.0eq) at 0° C., the reaction was stirred at 0° C. for 0.5 hour. Aftercompletion, the reaction mixture was added water (30 mL), then extractedwith EA (2×15 mL), the combined organic layer was washed with saturatedbrine (1×30 mL), then dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=5/1 to Petroleum ether/Ethylacetate/Methanol=3/1/0.1) to give benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(720 mg, 997 umol, 72% yield, 90.0% purity) as light yellow solid. LCMS[ESI, M+1]: 650.

Step C:2-[(2S)-4-[2-[[2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(670 mg, 1.03 mmol, 1.0 eq) in MeOH (15.0 mL) was added NH₃·MeOH (1.03mmol, 15.0 mL, 1.0 eq) and Pd/C (400 mg, 10% purity), the suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred under H₂ (15 Psi) at 20° C. for 1 hour. After completion, thereaction was filtered through a Celite, and the filtrate wasconcentrated to give2-[(2S)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(260 mg, 478 umol, 46% yield, 94.9% purity) as white solid. LCMS [ESI,M+1]: 516.

Step D:2-[(2S)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a mixture of2-[(2S)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(260 mg, 504 umol, 1.0 eq) in DCM (5.0 mL) was added DIEA (196 mg, 1.51mmol, 263 uL, 3.0 eq) and prop-2-enoyl prop-2-enoate (63.6 mg, 504 umol,1.0 eq) at 0° C., the reaction mixture was stirred at 20° C. for 0.5hour. After completion, the reaction mixture was quenched with MeOH (5mL), and concentrated. The residue was purified by prep-HPLC((Instrument: ACSWH-GX-H; Column: Gemini 150*25 5 u; Condition: water(0.05% ammonia hydroxide v/v)-ACN; Begin B: 42; End B: 72; Gradient Time(min): 12; 100% B Hold Time (min): 1.8; FlowRate (ml/min): 25), theobtained product was concentrated, and then under lyophilization. Theproduct2-[(2S)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 306, 65.6 mg, 115 umol, 23% yield, 99.8% purity) was obtainedas yellow solid. LCMS [ESI, M+1]: 570.

¹H NMR (400 MHz, chloroform-d) δ8.27-8.17 (m, 1H), 7.92-7.84 (m, 1H),7.63 (d, J=8.0 Hz, 1H), 7.56-7.49 (m, 2H), 7.45 (t, J=8.0 Hz, 1H), 7.17(d, J=6.8 Hz, 1H), 6.68-6.56 (m, 1H), 6.42 (dd, J=1.6, 16.8 Hz, 1H),5.86 (br d, J=10.4 Hz, 1H) 5.30-4.99 (m, 2H), 4.45 (dd, J=4.8, 10.8 Hz,1H), 4.35-4.21 (m, 3H), 4.15 (br d, J=13.6 Hz, 1H), 4.03 (br d, J=11.6Hz, 2H), 3.70-2.72 (m, 1H), 2.68-2.56 (m, 1H), 2.54 (s, 3H), 2.41-2.27(m, 1H), 2.10-1.90 (m, 1H).

Example 307

2-[4-[7-(2-fluoro-3-methoxy-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: tert-butyl2-(cyanomethyl)-4-[7-(2-fluoro-3-methoxy-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a mixture of tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(Intermediate 66, 300 mg, 636 umol, 1.00 eq),1-bromo-2-fluoro-3-methoxy-benzene (261 mg, 1.27 mmol, 2.00 eq),Pd₂(dba)₃ (117 mg, 127 umol, 0.20 eq), RuPhos (89.1 mg, 191 umol, 0.30eq) and Cs₂CO₃ (622 mg, 1.91 mmol, 3.00 eq) in toluene (30 mL) wasdegassed and purged with N₂ for 3 times, and then the mixture wasstirred at 90° C. for 16 hours under N₂ atmosphere. To the reactionmixture was added H₂O (200 mL) and ethyl acetate (250 mL). The separatedorganic phase was washed with brine (1×200 mL), dried over sodiumsulfate, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by reversed phase flash [water (0.1%FA)/acetonitrile]. The desired fractions were collected and neutralizedwith saturated NaHCO₃ solution and extracted with ethyl acetate (100mL). The separated organic layer was dried over sodium sulfate, filteredand concentrated under vacuum. tert-butyl2-(cyanomethyl)-4-[7-(2-fluoro-3-methoxy-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(210 mg, 353 umol, 55.4% yield, 100% purity) was obtained as a faintyellow solid. LCMS [ESI, M+1]: 596.

¹H NMR (400 MHz, chloroform-d) δ=7.00 (dt, J=1.6, 8.4 Hz, 1H), 6.74-6.56(m, 2H), 4.61 (br s, 1H), 4.44-4.34 (m, 1H), 4.28-4.10 (m, 3H), 4.01 (brd, J=13.6 Hz, 1H), 3.90 (s, 4H), 3.56-3.40 (m, 1H), 3.25 (br dd, J=3.6,13.6 Hz, 2H), 3.12 (br t, J=7.6 Hz, 1H). 2.98 (dt, J=2.8, 12.4 Hz, 1H),2.89-2.63 (m, 5H), 2.50 (s, 3H), 2.35-2.26 (m, 1H), 2.21-2.06 (m, 3H),1.90-1.68 (m, 3H), 1.60-1.42 (m, 9H).

Step B:2-[4-[7-(2-fluoro-3-methoxy-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl2-(cyanomethyl)-4-[7-(2-fluoro-3-methoxy-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(100 mg, 168 umol, 1.00 eq) in DCM (1 mL) was added TFA (1.63 g, 14.3mmol, 1.06 mL, 85.0 eq) at 0° C. under nitrogen atmosphere. The mixturewas stirred at 25° C. for 1 h and then the mixture was concentratedunder vacuum.2-[4-[7-(2-fluoro-3-methoxy-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(210 mg, crude, TFA) was obtained as a yellow oil. LCMS [ESI, M+1]: 496.

Step C:2-[4-[7-(2-fluoro-3-methoxy-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a mixture of2-[4-[7-(2-fluoro-3-methoxy-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(102 mg, crude TFA) and DIEA (216 mg, 1.67 mmol, 291 uL) in DCM (3 mL)was added prop-2-enoyl prop-2-enoate (16.9 mg, 134 umol) at 0° C. Afterstirring at 25° C. for 1 hour, the reaction mixture was quenched withsaturated NaHCO₃ solution (5 mL) at 0° C., and then extracted withCH₂Cl₂ (2×25 mL). The combined organic layers were washed with brine(1×50 mL), dried over sodium sulfate, filtered and concentrated undervacuum to give a residue. The residue was purified by prep-HPLC (column:Phenomenex Gemini 150*25 mm*10 um; mobile phase: [water (0.05% ammoniahydroxide v/v)-ACN]: B %: 38%-68%, 12 min),2-[4-[7-(2-fluoro-3-methoxy-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 307, 7.47 mg, 13.6 umol, two steps 17% yield, 100% purity) wasobtained as a white solid. LCMS [ESI, M+1]: 550.

¹H NMR (400 MHz, chloroform-d) δ=7.07-6.95 (m, 1H), 6.74-6.51 (m, 3H),6.45-6.34 (m, 1H), 5.83 (br d, J=10.6 Hz, 1H), 5.08 (br s, 1H), 4.38(dd, J=4.8, 10.5 Hz, 1H), 4.31-4.12 (m, 3H), 4.07 (br d, J=13.6 Hz, 1H),4.03-3.82 (m, 5H), 3.68-3.44 (m, 2H), 3.39-3.21 (m, 2H), 3.10 (br t,J=7.8 Hz, 2H), 2.95-2.61 (m, 5H), 2.48 (s, 3H), 2.33-2.23 (m, 1H),2.13-1.99 (m, 1H), 1.92-1.62 (m, 3H).

Example 308

2-(1-acryloyl-4-(7-(3-fluoro-2-methoxyphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: tert-butyl2-(cyanomethyl)-4-[7-(3-fluoro-2-methoxy-phenyl)-2-[[2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a mixture of tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(Intermediate 66, 300 mg, 636 umol, 1 eq),1-bromo-3-fluoro-2-methoxy-benzene (261 mg, 1.27 mmol, 2 eq), Pd₂(dba)₃(117 mg, 127 umol, 0.2 eq), RuPhos (89.1 mg, 191 umol, 0.3 eq) andCs₂CO₃ (622 mg, 1.91 mmol, 3 eq) in toluene (30 mL) was degassed andpurged with N₂ for 3 times, and then the mixture was stirred at 90° C.for 16 hours under N₂ atmosphere. To the reaction mixture, H₂O (200 mL)and ethyl acetate (250 mL) were added. The organic phase was separated,washed with brine (200 mL), dried over sodium sulfate, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by reversed phase flash [water (0.1% FA)/acetonitrile]. Thedesired fractions were collected, neutralized with saturated NaHCO₃solution and extracted with ethyl acetate (1×100 mL). The organic layerwas dried over sodium sulfate, filtered and concentrated under vacuum.Compound tert-butyl2-(cyanomethyl)-4-[7-(3-fluoro-2-methoxy-phenyl)-2-[[2)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(170 mg, 277 umol, 43.6% yield, 97.1% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 596.

¹H NMR (400 MHz, chloroform-d) δ=6.96 (dt, J=6.0, 8.0 Hz, 1H), 6.83-6.69(m, 1H), J=6.83-6.68 (m, 1H), 4.60 (br s, 1H), 4.39 (dd, J=4.8, 10.4 Hz,1H), 4.31-4.14 (m, 3H), 4.04 (br d, J=13.6 Hz, 2H), 3.94 (d, J=0.8 Hz,4H), 3.62-3.47 (m, 1H), 3.26 (br dd, J=4.0, 13.6 Hz, 2H), 3.12 (br t,J=7.6 Hz, 1H), 2.99 (dt, J=2.8, 12.0 Hz, 1H), 2.88-2.64 (m, 5H), 2.50(s, 3H), 2.36-2.24 (m, 1H), 2.22-2.07 (m, 2H), 1.94-1.64 (m, 3H),1.56-1.46 (m, 9H).

Step B:2-[4-[7-(3-fluoro-2-methoxy-phenyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a mixture of tert-butyl2-(cyanomethyl)-4-[7-(3-fluoro-2-methoxy-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(170 mg, 285 umol, 1 eq) in DCM (2.50 mL) was added TFA (651 mg, 5.71mmol, 423 uL, 20 eq) in one portion at 0° C. under N₂. After stirred at25° C. for 2 hours, the reaction mixture was concentrated under reducedpressure to give a residue. The crude product was used directly into thenext step without further purification. Compound2-[4-[7-(3-fluoro-2-methoxy-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(173 mg, 284 umol, 99.4% yield, TFA) was obtained as a brown solid. LCMS[ESI, M+1]: 496.

Step C:2-[4-[7-(3-fluoro-2-methoxy-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a mixture of2-[4-[7-(3-fluoro-2-methoxy-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(173 mg, 284 umol, 1 eq, TFA) and prop-2-enoyl prop-2-enoate (35.8 mg,284 umol, 1 eq) in DCM (3 mL) was added TEA (144 mg, 1.42 mmol, 198 uL,5 eq) in portion at 0° C. under N₂. After stirred at 25° C. for 0.5hour, the reaction mixture was quenched by adding saturated NaHCO₃ (1.5mL) at 0° C., and then diluted with water (2 mL) and extracted with DCM(20 mL×3). The combined organic layers were washed with water (15 mL×1),dried over sodium sulfate, filtered and concentrated under reducedpressure to give a residue. The crude product was purified by columnchromatography (Al₂O₃, Petroleum ether/Ethyl acetate=100/1 toMeOH/EA=1/2). The desired fractions were collected and concentratedunder reduced pressure. Then the residue was purified by prep-HPLC(column: Phenomenex Gemini 150×25 mm×10 um; mobile phase: [water (0.05%ammonia hydroxide v/v)-ACN]; B %: 48%-78%, 12 min). Title compound2-[4-[7-(3-fluoro-2-methoxy-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 308, 28.2 mg, 50.4 umol, 17.8% yield, 98.1% purity) wasobtained as a white solid. LCMS [ESI, M+1]: 550.

¹H NMR (400 MHz, chloroform-d) δ=6.97 (dt, J=6.0, 8.4 Hz, 1H), 6.83-6.76(m, 1H), 6.72 (d, J=8.0 Hz, 1H), 6.57 (br d, J=12.0 Hz, 1H), 6.40 (dd,J=1.6, 16.8 Hz, 1H), 5.83 (br d, J=10.8 Hz, 1H), 5.07 (br s, 1H), 4.56(br s, 1H), 4.39 (br dd, J=5.2, 10.4 Hz, 1H), 4.30-4.18 (m, 2H),4.18-4.06 (m, 2H), 4.04-3.96 (m, 1H), 3.95 (d, J=0.8 Hz, 3H), 3.73-3.46(m, 2H), 3.38-3.22 (m, 2H), 3.16-2.99 (m, 2H), 2.96-2.59 (m, 5H), 2.50(s, 3H), 2.36-2.22 (m, 1H), 2.16-1.98 (m, 1H), 1.94-1.68 (m, 3H).

Example 309

2-(1-acryloyl-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Insert: 1-bromo-8-methyl-naphthalene. To a solution of1,8-dibromonaphthalene (1 g, 3.50 mmol, 1 eq) in THF (20 mL) was addedMeLi (1.6 M in diethyl ether, 2.62 mL, 1.2 eq) at 0° C. dropwise. Afterstirring for 30 minutes at 0° C., iodomethane (3.38 g, 23.8 mmol, 1.48mL, 6.81 eq) was added dropwise. The mixture was warmed up to 25° C. andstirred for another 3 hours. The reaction mixture was quenched withwater (20 mL) and extracted with ethyl acetate (20 mL×3). The combinedorganic layers were washed with brine (20 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by prep-HPLC (column: Phenomenex Gemini C18 250*50mm*10 um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %:45%-70%, 28 MIN; 40% min). 1-bromo-8-methyl-naphthalene (340 mg, 1.49mmol, 43% yield, 97% purity) was obtained as a yellow solid afterlyophilisation.

¹H NMR (400 MHz, chloroform-d) δ=7.75 (dd, J=0.8, 7.2 Hz, 1H), 7.69 (dd,J=0.8, 8.0 Hz, 1H), 7.66-7.59 (m, 1H), 7.30-7.22 (m, 2H), 7.13 (t, J=8.0Hz, 1H), 3.05 (s, 3H).

Step A: tert-butyl2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrid[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.A mixture of 1-bromo-8-methyl-naphthalene (122 mg, 551 umol, 1.3 eq),tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(Intermediate 66, 200 mg, 424 umol, 1.3 eq), Cs₂CO₃ (345 mg, 1.06 mmol,2.5 eq), RuPhos (39.6 mg, 84.8 umol, 0.2 eq) and Pd₂(dba)₃ (77.7 mg,84.8 umol, 0.2 eq) in toluene (10 mL) was degassed and purged with Nifor 3 times, and then the mixture was stirred at 110° C. for 3 hoursunder N₂ atmosphere. The reaction mixture was diluted with water (20 mL)and extracted with ethyl acetate (20 mL×3). The combined organic layerswere washed with brine (20 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by reversed phase flash [water (0.1% formicacid)/acetonitrile)]. The mixture was adjusted pH=7 by additionsaturated NaHCO₃ aqueous solution and extracted with ethyl acetate (20mL×3). The combined organic layers were washed with brine (20 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to givetert-butyl2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(140 mg, 224 umol, 53% yield, 98% purity) as a yellow solid. LCMS [ESI,M+1]: 612.

¹H NMR (400 MHz, chloroform-d) δ=7.73-7.60 (m, 2H), 7.42 (dd, J=8.0,16.0 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H), 7.26-7.16 (m, 2H), 4.61 (br s,1H), 4.40 (br s, 1H), 4.30-4.16 (m, 2H), 4.10-3.71 (m, 4H), 3.58-3.45(m, 1H), 3.43-3.25 (m, 1H), 3.23-3.04 (m, 4H), 3.03-2.85 (m, 5H),2.83-2.55 (m, 4H), 2.49 (br s, 3H), 2.40-2.20 (m, 1H), 2.14-2.06 (m,1H), 1.92-1.71 (m, 2H), 1.55-1.44 (m, 9H).

Step B:2-[4-[7-(8-methyl-1-napthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(110 mg, 179 umol, 1 eq) in DCM (200 uL) was added TFA (307 mg, 2.70mmol, 199 uL, 15 eq). After stirred at 25° C. for 1 hour, the mixturewas concentrated under vacuum.2-[4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(112 mg, 179 umol, 100% yield, TFA) was obtained as a yellow oil andused to next step directly without purification. LCMS [ESI, M+1]: 512.

Step C:2-[4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(112 mg, 179 umol, 1 eq, TFA) in DCM (2 mL) was added TEA (181 mg, 1.79mmol, 249 uL, 10 eq) at 0° C. And then prop-2-enoyl prop-2-enoate (18.1mg, 143 umol, 0.8 eq) in DCM (1 mL) was added dropwise at 0° C. Theresulting mixture was stirred at 25° C. for 1 hour. The reaction mixturewas quenched with saturated NaHCO₃ aqueous solution (1 mL), diluted withwater (10 mL) and extracted with ethyl acetate (20 mL×3). The combinedorganic layers were washed with brine (20 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by column chromatography (Al₂O₃ Petroleumether/Ethyl acetate=10/1 to 1/3) and further purified by prep-HPLC(column Phenomenex Gemini 150*25 mm*10 um; mobile phase: [water (0.05%ammonia hydroxide v/v)-ACN]; B %: 55%-85%, 12 min). Title compound2-[4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 309, 16.2 mg, 28.4 umol, 16% yield, 99% purity) was obtained asa white solid after lyophilisation. LCMS [ESI, M+1]: 566.

SFC condition: “OJ=3S_5_5_40_3 ML Column: Chiralcel OJ=3 100×4.6 mmI.D., 3 um Mobile phase: ethanol (0.05% DEA) in CO₂ from 5% to 40% Flowrate: 3 mL/min Wavelength: 220 nm”.

¹H NMR (400 MHz, chloroform-d) δ=7.70 (br d, J=8.0 Hz, 1H), 7.65 (t,J=8.4 Hz, 1H), 7.46-7.38 (m, 1H), 7.34 (t, J=6.4 Hz, 1H), 7.27-7.17 (m,2H), 6.68-6.52 (m, J=9.9 Hz, 1H), 6.46-6.35 (m, 1H), 5.83 (br d, J=10.4Hz, 1H), 5.08 (br s, 1H), 4.59 (br s, 1H), 4.41-4.33 (m, 1H), 4.32-4.21(m, 1H), 4.20-4.04 (m, 3H), 4.03-3.82 (m, 2H), 3.85-3.67 (m, 1H),3.61-3.33 (m, 2H), 3.24-2.99 (m, 4H), 2.92 (s, 3H), 2.87-2.77 (m, 1H),2.71-2.59 (m, 2H), 2.47 (d, J=4.0 Hz, 3H), 2.34-2.20 (m, 1H), 2.13-1.98(m, 1H), 1.85-1.74 (m, 3H).

Example 310

2-(1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Insert: 1-bromo-8-chloronaphthalene. To a solution of perchloroethane(1.66 g, 6.99 mmol, 792 uL, 1 eq) in THF (30 mL) was added n-BuLi (2.5 Min hexane, 4.20 mL, 1.5 eq) at −78° C. dropwise. After stirring for anadditional 10 minutes at −78° C., 1,8-dibromonaphthalene (2 g, 6.99mmol, 1 eq) in THF (10 mL) was added. The mixture was warmed up to 25°C. and stirred for 3 hours. The reaction mixture was quenched with water(100 mL) and extracted with ethyl acetate (50 mL×3). The combinedorganic layers were washed with brine (50 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by prep-HPLC (column: Phenomenex Synergi Max-RP250*50 mm*10 um; mobile phase: [water (0.225% FA)-ACN]; B %: 41 ACN %-71ACN %, 30 min; 50% min). The mixture was adjusted PH=7 by addingsaturated NaHCO₃ aqueous solution and extracted with ethyl acetate (50mL×3). The combined organic layers were washed with brine (20 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to give1-bromo-8-chloronaphthalene (850 mg, 3.52 mmol, 50% yield, 100% purity)as a yellow solid.

¹H NMR (400 MHz, chloroform-d) δ=7.92 (dd, J=1.2, 7.2 Hz, 1H), 7.80(ddd, J=0.8, 8.0, 12.4 Hz, 2H), 7.67 (dd, J=1.2, 7.6 Hz, 1H), 7.38 (t,J=8.0 Hz, 1H), 7.32-7.25 (t, J=8.0 Hz, 1H).

Step A: tert-butyl4-[7-(8-chloro-1-naphthyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.A mixture of 1-bromo-8-chloro-naphthalene (133 mg, 551 umol, 1.3 eq),tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 424 umol, 1 eq), Cs₂CO₃ (345 mg, 1.06 mmol, 2.5 eq), RuPhos(39.6 mg, 84.8 umol, 0.2 eq) and Pd₂(dba)₃ (77.7 mg, 84.8 umol, 0.2 eq)in toluene (10 mL) was degassed and purged with N₂ for 3 times, and thenthe mixture was stirred at 110° C. for 3 hours under N₂ atmosphere. Thereaction mixture was diluted with water (20 mL) and extracted with ethylacetate (20 mL×3). The combined organic layers were washed with brine(20 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue. The residue was purified by reversed phaseflash [water (0.1% formic acid)/acetonitrile)]. The mixture was adjustedpH=7 by adding saturated NaHCO₃ aqueous solution and extracted withethyl acetate (20 mL×3). The combined organic layers were washed withbrine (20 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure. Compound tert-butyl4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(150 mg, 237 umol, 56% yield, 100% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 632.

¹H NMR (400 MHz, chloroform-d) δ 7.76 (d, J=8.4 Hz, 1H), 7.61 (t, J=7.6Hz, 1H), 7.52 (d, J=7.6 Hz, 1H), 7.49-7.39 (m, 1H), 7.34 (t, J=7.6 Hz,1H), 7.27-7.17 (m, 1H), 4.61 (br s, 1H), 4.51-4.33 (m, 2H), 4.22-4.15(m, 1H), 4.10-3.77 (m, 4H), 3.57 (br s, 1H), 3.41-3.01 (m, 6H),3.01-2.86 (m, 1H), 2.85-2.63 (m, 3H), 2.62-2.43 (m, 4H), 2.31 (br s, 1H)2.13-2.06 (m, 1H), 1.78 (br s, 2H), 1.52 (s, 9H).

Step B:2-[4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(150 mg, 237 umol, 1 eq) in DCM (200 uL) was added TFA (405 mg, 3.56mmol, 263 uL, 15 eq). The mixture was stirred at 25° C. for 1 hour. Thereaction mixture was concentrated under vacuum Compound2-[4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(153 mg, 236 umol, 100% yield, TFA) was obtained as a yellow oil andused to next step directly without purification. LCMS [ESI, M+1]: 532.

Step C:2-[4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(153 mg, 237 umol, 1 eq, TFA) in DCM (2 mL) was added TEA (239 mg, 2.37mmol, 329 uL, 10 eq) at 0° C. After addition, the prop-2-enoylprop-2-enoate (23.9 mg, 189 umol, 0.8 eq) in DCM (1 mL) was addeddropwise at 0° C. The resulting mixture was stirred at 25° C. for 1hour. The reaction mixture was quenched with saturated NaHCO₃ aqueoussolution (1 mL) and diluted with water (20 mL), extracted with ethylacetate (20 mL×3). The combined organic layers were washed with brine(20 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by prep-HPLC (column: PhenomenexGemini 150*25 mm*10 um; mobile phase: [water (0.05% ammonia hydroxidev/v)-ACN]; B %: 52%-82%, 12 min). Title compound2-[4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 310, 37 mg, 61.2 umol, 26% yield, 97% purity) was obtainedafter lyophilization as a white solid. LCMS [ESI, M+1]: 586.

SFC condition: “AD-3S_4_40_3 ML Column: Chiralpak AD-3 100×4.6 mm I.D.,3 um Mobile phase: 40% iso-propanol (0.05% DEA) in CO₂ Flow rate: 3mL/min Wavelength: 220 nm”.

¹H NMR (400 MHz, chloroform-d) δ=7.76 (d, J=8.0 Hz, 1H), 7.62 (t, J=7.2Hz, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.49-7.39 (m, 1H), 7.34 (t, J=8.0 Hz,1H), 7.27-7.18 (m, 1H), 6.59 (br s, 1H), 6.45-6.35 (m, 1H), 5.83 (br d,J=10.8 Hz, 1H), 5.07 (s, 1H), 4.84-4.25 (m, 3H), 4.22-3.72 (m, 5H),3.71-3.53 (m, 1H), 3.50-3.34 (m, 1H), 3.32-2.96 (m, 5H), 2.91-2.76 (m,1H), 2.70-2.52 (m, 2H), 2.48 (d, J=2.8 Hz, 3H), 2.33-2.20 (m, 1H),2.13-1.96 (m, 1H), 1.86-1.72 (m, 3H).

Example 311

2-(1-acryloyl-4-(7-(2-fluoronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step 1: 2-fluoronaphthalen-1-ol. To a solution of naphthalen-1-ol (2 g,13.9 mmol, 5.00 mL, 1 eq) in CH₃CN (50 mL) was added Select-F (4.91 g,13.9 mmol, 1 eq). The mixture was stirred at 20° C. for 3 hours. Themixture was concentrated under vacuum. The residue was purified bycolumn chromatography (SiO₂, PE/EA=3/1) and further purified byprep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase:[water (0.225% FA)-ACN]; B %: 40%-70%, 10 min). The mixture was adjustedPH=7 with saturated NaHCO₃ aqueous solution and extracted with ethylacetate (20 mL×3). The combined organic layers were washed with brine(20 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure. Compound 2-fluoronaphthalen-1-ol (400 mg, 2.44 mmol, 18%yield, 99% purity) was obtained as a yellow solid.

¹H NMR (400 MHz, chloroform-d) δ=8.21 (d, J=8.4 Hz, 1H), 7.80 (d, J=8.4Hz, 1H), 7.52 (t, J=7.2 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.39 (dd,J=5.2, 8.8 Hz, 1H), 7.31 (d, J=9.6 Hz, 1H), 5.58 (br s, 1H).

Step 2: (2-fluoro-1-naphthyl) trifluoromethanesulfonate. To a solutionof 2-fluoronaphthalen-1-ol (400 mg, 2.47 mmol, 1 eq) in DCM (10 mL) wasadded Tf₂O (765 mg, 2.71 mmol, 448 uL, 1.1 eq) and DIEA (637 mg, 4.93mmol, 859 uL, 2 eq) at 0° C. After stirred at 0° C. for 1 hour, thereaction mixture was diluted with ethyl acetate (20 mL) and washed withwater (20 mL×3). The combined organic layer was washed with brine (20mL), dried over Na₂SO₄, filtered and concentrated under reduced pressureto give a residue. The residue was purified by column chromatography(SiO₂, Petroleum ether/Ethyl acetate=50/1 to 3/1). Compound(2-fluoro-1-naphthyl) trifluoromethanesulfonate (500 mg, 1.65 mmol, 67%yield, 97% purity) was obtained as a colorless oil.

¹H NMR (400 MHz, chloroform-d) δ=8.07 (d, J=8.4 Hz, 1H), 7.95-7.85 (m,2H), 7.70 (t, J=7.6 Hz, 1H), 7.62-7.54 (m, 1H), 7.41 (t, J=9.2 Hz, 1H).

Step A: tert-butyl2-(cyanomethyl)-4-[7-(2-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.A mixture of (2-fluoro-1-naphthyl) trifluoromethanesulfonate (243 mg,827 umol, 1.3 eq), tert-butyl 2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(300 mg, 636 umol, 1 eq), Cs₂CO₃ (518 mg, 1.59 mmol, 2.5 eq), RuPhos(59.4 mg, 127 umol, 0.2 eq) and Pd₂(dba)₃ (116 mg, 127 umol, 0.2 eq) intoluene (10 mL) was degassed and purged with N₂ for 3 times, and thenthe mixture was stirred at 90° C. for 3 hours under N₂ atmosphere. Thereaction mixture was diluted with water (20 mL) and extracted with ethylacetate (20 mL×3). The combined organic layers were washed with brine(20 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue. The residue was purified by reversed phaseflash [water (0.1% formic acid)/acetonitrile)]. The mixture was adjustedPH=7 by adding saturated NaHCO₃ aqueous solution and extracted withethyl acetate (20 mL×3). The combined organic layers were washed withbrine (20 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure. Compound tert-butyl2-(cyanomethyl)-4-[7-(2-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(100 mg, 155 umol, 25% yield, 96% purity) was obtained as a yellow solidLCMS [ESI, M+1]: 616.

¹H NMR (400 MHz, chloroform-d) δ 8.33 (br s, 1H), 7.84 (d, J=7.76 Hz,1H), 7.75-7.64 (m, 1H), 7.57-7.41 (m, 2H), 7.25-7.21 (m, 1H), 4.63 (brs, 1H), 4.47-4.16 (m, 4H), 4.13-3.82 (m, 4H), 3.61-3.25 (m, 3H),3.20-2.90 (m, 4H), 2.81-2.56 (m, 4H), 2.49 (s, 3H), 2.38-2.19 (m, 1H),2.14-2.06 (m, 1H), 1.88-1.69 (m, 2H), 1.53 (s, 9H).

Step B:2-[4-[7-(2-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl2-(cyanomethyl)-4-[7-(2-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(100 mg, 162 umol, 1 eq) in DCM (200 uL) was added TFA (278 mg, 2.44mmol, 180 uL, 15 eq). The mixture was stirred at 25° C. for 1 hour. Thereaction mixture was concentrated under vacuum. Compound2-[4-[7-(2-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(102 mg, 162 umol, 100% yield, TFA) was obtained as a yellow oil andused to next step directly without purification. LCMS [ESI, M+1]: 516.

Step C:2-[4-[7-(2-fluoro-1-naphthyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[4-[7-(2-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(102 mg, 197 umol, 1 eq, TFA) in DCM (2 mL) was added TEA (200 mg, 1.98mmol, 275 uL, 10 eq) at 0° C. After addition, the prop-2-enoylprop-2-enoate (19.9 mg, 158 umol, 0.8 eq) in DCM (1 mL) was addeddropwise at 0° C. After stirred at 25° C. for 1 hour, the reactionmixture was quenched with saturated NaHCO₃ aqueous solution (1 mL) anddiluted with water (20 mL), extracted with ethyl acetate (20 mL×3). Thecombined organic layers were washed with brine (20 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by prep-HPLC (column: PhenomenexGemini 150*25 mm*10 um; mobile phase: [water (0.05% ammonia hydroxidev/v)-ACN]; B %: 52%-82%, 12 min). Title compound2-[4-[7-(2-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 311, 11 mg, 18.9 umol, 9.6% yield, 98% purity) was obtainedafter lyophilization as a white solid. LCMS [ESI, M+1]: 570.

SFC condition: “OD-3S_3_40_3 ML Column: Chiralcel OD-3 100×4.6 mm I.D.,3 um Mobile phase: 40% methanol (0.05% DEA) in CO₂ Flow rate: 3 mL/minWavelength: 220 nm”.

¹H NMR (400 MHz, chloroform-d) δ=8.34 (br s, 1H), 7.84 (d, J=8.0 Hz,1H), 7.69 (dd, J=4.4, 8.8 Hz, 1H), 7.52 (t, J=7.2 Hz, 1H), 7.47 (t,J=6.8 Hz, 1H), 7.29-7.25 (m, 1H), 6.65-6.50 (m, J=10.5 Hz, 1H), 6.40(dd, J=1.2, 16.8 Hz, 1H), 5.84 (br d, J=10.4 Hz, 1H), 5.11 (br s, 1H),4.65 (s, 1H), 4.43-3.85 (m, 7H), 3.81-3.30 (m, 3H), 3.24-2.95 (m, 3H),2.94-2.56 (m, 4H), 2.47 (s, 3H), 2.36-2.20 (m, 1H), 2.13-1.97 (m, 1H),1.93-1.75 (m, 3H).

Example 312

2-[4-[2-[[(2S,4R)-4-hydroxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: methyl (2S,4R)-4-[tert-butyl(diphenyl)silyl]oxopyrrolidine-2-carboxylate. To a solution of methyl(2S,4R)-4-hydroxypyrrolidine-2-carboxylate (10 g, 55.1 mmol, 1 eq, HCl)in ethyl acetate (10 mL) were added imidazole (7.50 g, 110 mmol, 2 eq)and TBDPSCl (16.7 g, 60.6 mmol, 15.6 mL, 1.1 eq). The mixture wasstirred at 25° C. for 16 hours. The precipitate was filtered off. Thefiltrate was concentrated under reduced pressure and the residue wasdissolved with ethyl acetate (200 mL) and water (100 mL). The organicphase was washed with brine (1×100 mL), dried over magnesium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by column chromatography over silica gel (petroleum ether/ethylacetate 10/1 to 1/1). The desired fractions were collected andconcentrated under vacuum to give methyl(2S,4R)-4-[tert-butyl(diphenyl)silyl] oxopyrrolidine-2-carboxylate (2.9g, 7.41 mmol, 13% yield, 98% purity) a colorless oil. LCMS [ESI, M+1]:384.

¹H NMR (400 MHz, chloroform-d) δ=7.64 (dt, J=1.2, 7.2 Hz, 4H), 7.47-7.35(m, 6H), 4.40 (td, J=2.4, 4.8 Hz, 1H), 4.07 (t, J=8.0 Hz, 1H), 3.70 (s,3H), 3.03-2.96 (m, 1H), 2.96-2.89 (m, 1H), 2.17-2.07 (m, 1H), 1.84-1.77(m, 1H), 1.07 (s, 9H).

Step B: methyl (2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidine-2-carboxylate. To a solution of methyl(2S,4R)-4-[tert-butyl(diphenyl)silyl] oxy pyrrolidine-2-carboxylate (2.7g, 7.04 mmol, 1 eq) and formaldehyde (37% aqueous, 2.86 g, 35.2 mmol,2.62 mL, 5 eq) in MeOH (20 mL) was added CH₃COOH (423 mg, 7.04 mmol, 403uL, 1 eq) and NaBH₃CN (1.77 g, 28.2 mmol, 4 eq). The mixture was stirredat 25° C. for 1 hr. The mixture was diluted with ethyl acetate (200 mL)and washed with water (2×100 mL) and brine (1×100 mL). The separatedorganic layer was dried over sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by column chromatography oversilica gel (petroleum ether/ethyl acetate 20/1 to 3/1). The desiredfractions were collected and concentrated under vacuum to give methyl(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidine-2-carboxylate (2.4 g, 5.71 mmol, 81% yield,94.6% purity) as a colorless oil. LCMS [ESI, M+1]: 398.

¹H NMR (400 MHz, chloroform-d) δ=7.63 (ddd, J=1.2, 4.0, 7.6 Hz, 4H),7.46-7.32 (m, 6H), 4.47-4.39 (m, 1H), 3.71 (s, 3H), 3.32 (t, J=8.4 Hz,1H), 3.24 (dd, J=6.0, 9.6 Hz, 1H), 2.43-2.40 (m, 1H), 2.40 (s, 3H),2.23-2.00 (m, 2H), 1.07 (s, 9H).

Step C: [(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methanol.To a solution of methyl(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidine-2-carboxylate(2.20 g, 5.53 mmol, 1.00 eq) in THF (40 mL) was added LiAlH₄ (840 mg,22.1 mmol, 4.00 eq) at 0° C. The mixture was stirred at 0° C. for 1hour. The mixture was quenched with water (1.00 mL), sodium hydroxidesolution (15.0%, 2.00 mL) and water (3.00 mL). The precipitate wasfiltered off and the filtrate was concentrated under vacuum. The residuewas purified by column chromatography (Al₂O₃, methanol/ethyl acetate1/10) to give [(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methanol(1.70 g, 4.55 mmol, 82% yield) as a colorless oil. LCMS [ESI, M+1]: 370.

¹H NMR (400 MHz, chloroform-d) δ 7.68-7.61 (m, 4H), 7.46-7.35 (m, 6H),4.35-4.26 (m, 1H), 3.62 (dd, J=3.2, 10.8 Hz, 1H), 3.34 (dd, J=2.0, 10.8Hz, 1H), 3.14 (dd, J=5.6, 10.0 Hz, 1H), 2.78-2.70 (m, 1H), 2.43 (dd,J=6.0, 9.6 Hz, 1H), 2.33 (s, 3H), 2.02-1.93 (m, 1H), 1.92-1.84 (m, 1H),1.06 (s, 9H).

Step D: tert-butyl 4-[2-[[(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.To a solution of tert-butyl2-(cyanomethyl)-4-[2-methylsulfinyl-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.30 g, 531 umol, 1.00 eq) and[(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methanol(295 mg, 797 umol, 1.50 eq) in THF (5 mL) was added t-BuONa (102 mg,1.06 mmol, 2.00 eq) at 0° C. After stirred at 0° C. for 0.5 h, themixture was adjusted to pH=7 by HCl solution (1.00 M, 0.40 mL) andextracted with ethyl acetate (3×10.0 mL). The organic layers were washedwith brine (1×10.0 mL), dried over Na₂SO₄, filtered and concentratedunder vacuum. The residue was purified by column chromatography (Al₂O₃,petroleum ether/ethyl acetate=1/3) to give tert-butyl4-[2-[[(2S,4R)-4-[tert-butyl (diphenyl)silyl]oxy-1-methyl-pyrrolidin-2yl]methoxy]-7-[2-(trifluormethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(0.22 g, 238 umol, 45% yield) as a white solid. LCMS [ESI, M+1]: 870.

¹H NMR (400 MHz, chloroform-d) δ=7.68 (br d, J=8.0 Hz, 1H), 7.66-7.61(m, 4H), 7.57 (br t, J=7.2 Hz, 1H), 7.44-7.34 (m, 7H), 7.33-7.28 (m,1H), 4.61 (br s, 1H), 4.45-4.28 (m, 2H), 4.09-3.95 (m, 4H), 3.87 (br d,J=12.8 Hz, 1H), 3.28-3.15 (m, 4H), 3.10 (ddd, J=3.6, 7.2, 12.0 Hz, 2H),3.02-2.93 (m, 1H), 2.88-2.67 (m, 4H), 2.48 (s, 3H), 2.45-2.34 (m, 2H),2.14-2.07 (m, 1H), 1.94-1.80 (m, 1H), 1.52 (s, 9H), 1.06 (s, 9H).

Step E:2-[4-[2-[[(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.A mixture of tert-butyl 4-[2-[[(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(0.08 g, 91.9 umol, 1.00 eq) and TFA (157 mg, 1.38 mmol, 102 uL, 15.0eq) in dichloromethane (150 uL) was stirred at 10° C. for 1 hour. Themixture was concentrated under vacuum to give2-[4-[2-[[(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(81.3 mg, crude, TFA) as a yellow oil and used into next step withoutfurther purification. LCMS [ESI, M+1]: 770.

Step F:2-[4-[2-[[(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of 2-[4-[2-[[(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(0.08 g, crude, TFA) and Et₃N (91.6 mg, 905 umol, 125.96 uL) indichloromethane (2.00 mL) was added prop-2-enoyl prop-2-enoate (11.4 mg,90.5 umol) at −40° C. After stirred at 20° C. for 0.5 h, the mixture wasquenched with water (0.20 mL) and concentrated under vacuum. The residuewas purified by column chromatography (Al₂O₃, methanol/ethylacetate=1/10). The desired fractions were collected and concentratedunder vacuum to give2-[4-[2-[[(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enyl-piperazin-2-yl]acetonitrile(0.06 g, 65.5 umol, two steps 72% yield) as a yellow oil. LCMS [ESI,M/2+1]: 412.

Step G:2-[4-[2-[[(2S,4R)-4-hydroxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.A mixture of2-[4-[2-[[(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(0.05 g, 60.7 umol, 1.00 eq) and TBAF (1.00 M, 607 uL, 10.0 eq) in THF(0.50 mL) was stirred at 20° C. for 1 hour. The mixture was concentratedunder vacuum. The residue was purified by column chromatography (Al₂O₃,ethyl acetate/methanol=3/1) and reversed phase flash [water (FA,0.10%)/acetonitrile], then further purified by prep-HPLC column: BostonpH-lex 150*25 10 um; mobile phase: [water (0.10%, TFA)-ACN]; B %:31%-61%, 10 min and column: Phenomenex Gemini 150*25 mm*10 um; mobilephase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 42%-72%, 12 min.The desired fractions were collected and lyophilized to give titlecompound2-[4-[2-[[(2S,4R)-4-hydroxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 312, 3.70 mg, 6.30 umol, 10% yield, 99.7% purity) as a whitesolid LCMS [ESI, M+1]: 586.

¹H NMR (400 MHz, chloroform-d) δ=7.69 (d, J=8.0 Hz, 1H), 7.58 (t, J=8.0Hz, 1H), 7.41 (d, =8.0 Hz, H), 7.30 (t, J=8.0 Hz, 1H), 6.57 (br d,J=10.8 Hz, 1H), 6.39 (dd, J=1.6, 16.4 Hz, 1H), 5.83 (br d, J=10.8 Hz,1H), 5.06 (br s, 1H), 4.49-4.42 (m, 1H), 4.37 (ddd, J=3.2, 4.8, 10.8 Hz,1H), 4.25-4.17 (m, 1H), 4.15-4.06 (m, 3H), 3.97 (br d, J=10.8 Hz, 1H),3.60 (br s, 1H), 3.43 (dd, J=6.0, 10.0 Hz, 1H), 3.33 (br s, 1H),3.23-3.16 (m, 1H), 3.15-3.06 (m, 2H), 3.04-2.89 (m, 3H), 2.88-2.66 (m,4H), 2.48 (s, 3H), 2.33 (dd, J=6.0, 10.0 Hz, 1H), 2.13-1.93 (m, 2H).

Example 313

2-[4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-[5-(trifluoromethyl)-1H-indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]

Step A:2-[[4-bromo-5-(trifluoromethyl]indazol-1-yl]methoxy]ethyl]-trimethyl-silane.To a solution of 4-bromo-5-(trifluoromethyl)-1H-indazole (1 g, 3.77mmol, 1 eq) in DMF (45 mL) was added NaH (181 mg, 4.53 mmol, 60.0%purity, 1.2 eq) at 0° C. After being stirred at 0° C. for 1 hour, asolution of SEM-Cl (818 mg, 4.91 mmol, 868 uL, 1.3 eq) in DMF (15 mL)was added dropwise. The mixture was warmed to 20° C. and stirred for 1hour. The mixture was quenched with saturated aqueous ammonium chloridesolution (50 mL), diluted with water (100 mL) and then extracted withethyl acetate (2×50 mL). The combined organic layers were dried overNa₂SO₄, filtered and concentrated under vacuum. The residue was purifiedby silica gel chromatography (PE:EtOAc from 1:0 to 100:1) to give2-[[4-bromo-5-(trifluoromethyl)indazol-1-yl]methoxy]ethyl-trimethyl-silane(430 mg, 1.03 mmol, 27.4% yield, 95.0% purity) as a colorless oil.

¹H NMR (400 MHz, chloroform-d) δ=8.18 (s, 1H), 7.74-7.66 (m, 1H),7.63-7.56 (m, 1H), 5.76 (s, 2H), 3.59-3.49 (m, 2H), 0.93-0.86 (m, 2H),−0.01-−0.08 (m, 9H).

Step B: tert-butyl4-[3-(cyanomethyl)piperazin-1-yl]-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate.To the solution of tert-butyl2-methylsulfanyl-4-(trifluoromethylsulfonyloxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(3.59 g, 8.36 mmol, 1 eq), 2-piperazin-2-ylacetonitrile (Intermediate62, 1.99 g, 10.0 mmol, 1.2 eq, 2HCl) in DMF (30 mL) was added DIEA (2.16g 16.7 mmol, 2.91 mL, 2 eq), then the mixture was heated to 80° C. andstirred at 80° C. for 2 hours. Water (80 mL) was added into the mixture.The resulting mixture was diluted with EtOAc (20 mL) and extracted withEtOAc (5×60 mL). The combined organic layers were washed with brine (80mL), dried over anhydrous Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by reversed phase flash column(ACN/Water (0.1% FA)=40%) to give tert-butyl4-[3-(cyanomethyl)piperazin-1-yl]-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(2.37 g, 5.27 mmol, 63.1% yield, 90.0% purity) as a brown solid. LCMS[ESI, M+1]: 405.

Step C: tert-butyl4-[4-benzyloxycarbonyl-3-cyanomethyl)piperazin-1-yl]-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate.To the solution of tert-butyl4-[3-(cyanomethyl)piperazin-1-yl]-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(2.37 g, 5.86 mmol, 1 eq), NaHCO₃ (1.48 g, 17.6 mmol, 684 uL, 3 eq) inEtOAc (30 mL) and Water (15 mL) was added CbzCl (2.00 g, 11.7 mmol, 1.67mL, 2 eq) dropwise, then the mixture was stirred at 25° C. for 13 hours.The mixture was diluted with EtOAc (15 mL) and extracted with EtOAc(2×15 mL). The combined organic layers were washed with brine (15 mL).The combined organic layers were dried over anhydrous Na₂SO₄, filteredand concentrated under vacuum. The residue was purified by silica gelchromatography (PE:EtOAc=20:1˜0:1) to give tert-butyl4-[4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(2.91 g, 5.13 mmol, 87.6% yield, 95.0% purity) as a yellow solid. LCMS[ESI, M+1]: 539.

Step D: tert-butyl4-[4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate.To the solution of tert-butyl4-[4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(2.91 g, 5.40 mmol, 1 eq) in EtOAc (60 mL) and ACN (20 mL) was addedm-CPBA (1.10 g, 5.40 mmol, 85.0% purity, 1 eq) at 0° C., then themixture was stirred at 0° C. for 1 hour. The reaction mixture wasquenched by saturated Na₂S₂O₃ (30 mL) at 0° C., then extracted withEtOAc (50 mL). The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated under vacuum. The residue was purified byreversed phase flash column (ACN/Water (0.1% NH₃·H₂O)=62%) to givetert-butyl4-[4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(2.65 g, 4.73 mmol, 87.6% yield, 99.0% purity) as a white solid. LCMS[ESI, M+1]: 555.

Step E: tert-butyl4-[4-benzyloxycarbonyl-3-(cyanoethyl)piperazin-1-yl]-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate.To the solution of tert-butyl4-[4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(2.2 g, 3.97 mmol, 1 eq), [(3R)-1-methylpyrrolidin-3-yl]methanol (914mg, 7.93 mmol, 2 eq) in toluene (44 mL) was added t-BuONa (572 mg, 5.95mmol, 1.5 eq) at 0° C., then the mixture was stirred at 0° C. for 0.5hour. Water (15 mL) was added into the mixture. The resulting mixturewas diluted with EtOAc (10 mL) and extracted with EtOAc (2×20 mL). Thecombined organic layers were washed with brine (20 mL). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by reversed phaseflash column (ACN/Water (0.1% FA)=45%) to give tert-butyl4-[4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(1.64 g, 2.52 mmol, 63.5% yield, 93.0% purity) as a white solid. LCMS[ESI, M+1]: 605.

¹H NMR (400 MHz, chloroform-d) δ=7.44-7.31 (m, 5H), 5.19 (s, 2H),4.71-4.54 (m, 2H), 4.35 (br d, J=19.2 Hz, 1H), 4.24-4.16 (m, 2H),4.11-3.92 (m, 2H), 3.79 (br d, J=12.4 Hz, 2H), 3.28 (br d, J=12.8 Hz,3H), 2.98 (dt, 1=3.2, 12.4 Hz, 1H), 2.87-2.44 (m, 8H), 2.36 (s, 3H),2.12-2.06 (m, 1H), 1.87 (br s, 2H), 1.49 (s, 9H).

Step F: benzyl 2-(cyanomethyl)-4[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To the solution of tert-butyl4-[4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(1.64 g, 2.71 mmol, 1 eq) in dioxane (30 mL) was added HCl/dioxane (4 M,30 mL, 44.32 eq) at 0° C., then the mixture was stirred at 25° C. for 1hour. The reaction mixture was concentrated under vacuum. The residuewas purified by reversed phase flash column (ACN/Water (0.1% FA) 35.5%)to give benzyl2-(cyanomethyl)-4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.95 g, 1.78 mmol, 65.9% yield, 95.0% purity) as a white solid. LCMS[ESI, M+1]: 506.

¹H NMR (400 MHz, chloroform-d) δ=7.43-7.32 (m, 5H), 5.19 (s, 2H), 4.66(br s, 1H), 4.25-4.07 (m, 3H), 4.01-3.91 (m, 3H), 3.83 (br d, J=13.6 Hz,1H), 3.38-3.18 (m, 2H), 3.16-3.07 (m, 1H), 3.03-2.92 (m, 2H), 2.81 (brs, 1H), 2.75-2.65 (m, 3H), 2.60 (br d, J=5.6 Hz, 3H), 2.55-2.45 (m, 2H),2.36 (s, 3H), 2.14-1.97 (m, 1H), 1.68-1.54 (m, 2H).

Step G: benzyl2-(cyanomethyl)-4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To the solution of benzyl2-(cyanomethyl)-4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(510 mg, 1.01 mmol, 1 eq),2-[[4-bromo-5-(trifluoromethyl)indazol-1-yl]methoxy]ethyl-trimethyl-silane(399 mg, 1.01 mmol, 1 eq), RuPhos (188 mg, 403 umol, 0.4 eq) and Cs₂CO₃(986 mg, 3.03 mmol, 3 eq) in toluene (10 mL) was added Pd₂(dba)₃ (185mg, 202 umol, 0.2 eq) under N₂, the suspension was degassed under vacuumand purged with Na several times. The mixture was warmed to 90° C. andstirred at 90° C. for 14 hours. The reaction mixture filtered, thefilter cake was washed with EtOAc (2×15 mL). The filtrate wasconcentrated under vacuum. The residue was purified by reversed phaseflash column (ACN/Water (0.1% FA)=55%) to give benzyl2-(cyanomethyl)-4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(365 mg 423 umol, 41.9% yield, 95.0% purity) as a brown solid. LCMS[ESI, M+1]: 820.

¹H NMR (400 MHz, chloroform-d) δ=8.15 (s, 1H), 7.70 (d, J=8.8 Hz, 1H),7.52 (d, J=8.8 Hz, 1H), 7.42-7.33 (m, 5H), 5.76 (s, 2H), 5.24-5.16 (m,2H), 4.70 (br s, 1H), 4.42-4.27 (m, 2H), 4.21 (br d, J=6.8 Hz, 2H), 4.06(br d, J=10.8 Hz, 1H), 3.90 (br d, J=12.4 Hz, 1H), 3.61-3.54 (m, 2H),3.50-3.38 (m, 2H), 3.31 (br d, J=11.6 Hz, 2H), 3.10-2.99 (m, 1H), 2.86(br s, 2H), 2.81-2.66 (m, 4H), 2.65-2.57 (m, 1H), 2.56-2.44 (m, 2H),2.36 (s, 3H), 2.12-2.06 (m, 1H), 2.04-1.96 (m, 1H), 1.69-1.56 (m, 1H),0.95-0.87 (m, 2H), −0.03-−0.10 (m, 9H).

Step H:2-[4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.NH₃ was bubbled into MeOH (6 mL) for 5 minutes. To the solution wasadded benzyl2-(cyanomethyl)-4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(310 mg, 378 umol, 1 eq), Pd/C (150 mg, 10.0% purity) under N₂. Thesuspension was degassed under vacuum and purged with H₂ several times.The mixture was stirred under H₂ (15 psi) at 28° C. for 1 hour. Themixture filtered, the filtrate was concentrated under vacuum. Theresidue was used to next step directly without further purification.Compound2-[4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(165 mg, 240 umol, 63.6% yield, 100% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 686.

Step I:2-[4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To the solution of2-[4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(190 mg, 277 umol, 1 eq), DIEA (107 mg, 831 umol, 145 uL, 3 eq) in DCM(4 mL) was added prop-2-enoyl prop-2-enoate (41.9 mg, 332 umol, 1.2 eq)at 0° C., then the mixture was stirred at 28° C. for 1 hour. Thereaction mixture was quenched by Water (1 mL) and extracted with DCM(3×4 mL). The combined organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated under vacuum. The residue was used to nextstep directly without further purification. Compound2-[4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(230 mg, 233 umol, 84.2% yield, 75.0% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 740.

Step J:2-[4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-[5-(trifluoromethyl)-1H-indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To the solution of2-[4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(220 mg, 297 umol, 1 eq) in DCM (1 mL) was added TFA (1.70 g, 14.9 mmol,1.10 mL, 50 eq), the mixture was stirred at 28° C. for 1 hour. Thereaction mixture was basified by saturated NaHCO₃ (12 mL) to PH=8. Theresulting mixture was extracted with DCM:MeOH (10:1) (3×15 mL). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by silica gelchromatography (EtOAc:MeOH=100:1˜10:1), then the residue was purified byprep-HPLC (column: Gemini 150*25 5 u; mobile phase: [water (0.05%ammonia hydroxide v/v)-ACN]; B %: 44%-74%, 12 min) to give2-[4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-[5-(trifluoromethyl)-1H-indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 313, 1.23 mg, 2.01 umol, 6.74e-1% yield, 99.4% purity) as awhite solid. LCMS [ESI, M+1]: 610.

¹H NMR (400 MHz, methanol-d₄) δ=8.38 (s, 1H), 7.70 (d, J=8.8 Hz, 1H),7.57 (d, J=8.8 Hz, 1H), 6.84 (br s, 1H), 6.31 (br d, J=16.8 Hz, 1H),5.86 (br d, J=10.8 Hz, 1H), 5.13 (br s, 1H), 4.62 (br s, 1H), 4.37-4.20(m, 5H), 4.14 (br d, J=11.6 Hz, 1H), 3.64 (br s, 1H), 3.50 (br d, J=4.8Hz, 2H), 3.41-3.34 (m, 1H), 3.29-3.16 (m, 2H), 3.03 (br d, J=6.4 Hz,1H), 2.94 (br s, 2H), 2.88-2.80 (m, 1H), 2.80-2.72 (m, 1H), 2.69 (br t,J=6.8 Hz, 2H), 2.58-2.51 (m, 1H), 2.43 (s, 3H), 2.17-2.06 (m, 1H),1.75-1.64 (m, 1H).

Example 314

2-[(2S)-4-[7-(3-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: benzyl(2S)-2-(cyanomethyl)-4-[7-(3-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution ofbenzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl,]piperazine-1-carboxylate(Intermediate 65, 900 mg, 1.78 mmol, 1.0 eq), Pd₂(dba)₃ (245 mg, 267umol, 0.15 eq), RuPhos (166 mg, 3.56 umol, 0.20 eq) and Cs₂CO₃ (1.16 g,3.56 mmol, 2.0 eq) in toluene (10.0 mL) was added (3-methoxy-1-naphthyl)trifluoromethanesulfonate (Intermediate 30, 1.09 g, 3.56 mmol, 2.0 eq).The mixture was stirred at 100° C. for 5 hours. After completion, themixture was added water (20.0 mL) and extracted with EA (20 mL×3). Theorganic layer was dried over Na₂SO₄, filtered and concentrated. Theobtained product was purified by column chromatography (SiO₂,PE:EA=10:1-EA:MeOH=10:1) to give benzyl(2S)-2-(cyanomethyl)-4-[7-(3-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1.0 g, 1.42 mmol, 79% yield, 93.8% purity) as yellow solid.

¹H NMR (400 MHz, Chloroform-d) δ 8.08 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.0Hz, 1H), 7.48-7.32 (m, 7H), 6.91 (d, J=2.0 Hz, 1H), 6.80 (d, J=2.0 Hz,1H), 5.27-5.15 (m, 2H), 4.70 (br s, 1H), 4.51-4.33 (m, 1H), 4.30-4.03(m, 5H), 3.94-3.87 (m, 3H), 3.53-3.40 (m, 1H), 3.32 (br d, J=12.4 Hz,3H), 3.16 (br t, J=7.6 Hz, 1H), 3.06 (dt, J=3.6, 12.6 Hz, 1H), 2.97-2.72(m, 6H), 2.52 (s, 3H), 2.39-2.28 (m, 1H), 2.15-2.06 (m, 1H), 1.93-1.74(m, 3H).

Step B:2-[(2S)-4-[7-(3-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.NH₃ was bubbled into MeOH (50.0 mL) at −60° C. for 30 minutes. Thenbenzyl(2S)-2-(cyanomethyl)-4-[7-(3-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1.0 g, 1.51 mmol, 1.0 eq) and Pd/C (1.0 g, 10% purity) was added to theabove liquid under N₂ atmosphere. The suspension was degassed and purgedwith H, for 3 times. The mixture was stirred under H₂ (15 Psi) at 20° C.for 2 hours. After completion, the mixture was filtered with Celite andconcentrated under vacuum. The product2-[(2S)-4-[7-(3-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(600 mg, crude) as yellow oil. LCMS [ESI, M+1]: 528.

Step C:2-[(2S)-4-[7-(3-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(3-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(600 mg, 1.14 mmol, 1.0 eq) and DIEA (882 mg, 6.82 mmol, 1.19 mL, 6.0eq) in DCM (6.0 mL) was added prop-2-enoyl prop-2-enoate (143 mg, 1.14mmol, 1.0 eq). The mixture was stirred at 0° C. for 0.5 hour. Aftercompletion, the mixture was quenched with MeOH (100 mg) and concentratedunder vacuum. The obtained product was purified by prep-HPLC (column:Phenomenex Gemini 150*25 mm*10 um; mobile phase: [water (0.05% ammoniahydroxide v/v)-ACN]; B %: 52%-80%, 12 min) to give the title compound2-[(2S)-4-[7-(3-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 314, 90.5 mg, 155 umol, 14.0% yield, 99.5% purity) as whitesolid. LCMS [ESI, M+1]: 582.

¹H NMR (400 MHz, Chloroform-d) δ 8.09 (d, J=8.4 Hz, 1H), 7.75 (d, J=8.4Hz, 1H), 7.45 (t, J=7.2 Hz, 1H), 7.36 (t, J=7.6 Hz, 1H), 6.91 (d, J=2.0Hz, 1H), 6.81 (d, J 2.4 Hz, 1H), 6.68-6.53 (m, 1H), 6.41 (dd, J=1.6,16.8 Hz, 1H), 5.84 (br d, J=10.4 Hz, 1H), 5.19-4.50 (m, 1H), 4.40 (dd,J=4.8, 10.4 Hz, 1H), 4.31-4.08 (m, 4H), 4.07-3.85 (m, 5H), 3.79-3.41 (m,2H), 3.41-3.22 (m, 2H), 3.20-3.04 (m, 2H), 3.02-2.75 (m, 4H), 2.72-2.65(m, 1H), 2.49 (s, 3H), 2.33-2.24 (m, 1H), 2.11-2.01 (m, 1H), 1.90-1.71(m, 3H).

Example 315

2-[(2S)-4-[2-[[(2S,4R)-4-hydroxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: benzyl(2S)-4-[2-[[(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[2-methylsulfinyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(Intermediate 64, 0.90 g, 1.55 mmol, 1.00 eq) and[(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methanol(687 mg, 1.86 mmol, 1.20 eq) in THF (20.0 mL) was added t-BuONa (298 mg,3.10 mmol, 2.00 eq) at 0° C. After stirred at 25° C. for 1 hour, themixture was diluted with ethyl acetate (50.0 mL), washed with water(30.0 mL) and brine (1×30.0 mL), dried over Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by columnchromatography (Al₂O₃, methanol/ethyl acetate=1/10) to give benzyl(2S)-4-[2-[[(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(0.90 g, 873 umol, 56% yield) as a yellow solid. LCMS [ESI, M/2+1]: 443.

¹H NMR (400 MHz, chloroform-d) δ=8.24-8.18 (m, 1H), 7.90-7.83 (m, 1H),7.71-7.57 (m, 5H), 7.53-7.47 (m, 2H), 7.45-7.35 (m, 12H), 7.14 (br d,J=7.6 Hz, 1H), 5.21 (s, 2H), 4.68 (br s, 1H), 4.43-4.36 (m, 1H), 4.33(br dd, =4.8, 10.8 Hz, 1H), 4.26 (br s, 2H), 4.16-4.03 (m, 3H), 3.93 (brd, J=12.8 Hz, 1H), 3.47 (br s, 1H), 3.30 (br d, J=10.4 Hz, 3H), 3.17 (brdd, J=6.0, 10.0 Hz, 1H), 3.11-2.96 (m, 3H), 2.84 (br s, 2H), 2.78-2.70(m, 1H), 2.48-2.37 (m, 4H), 2.11 (ddd, J=4.8, 8.4, 12.8 Hz, 1H),1.96-1.82 (m, 1H), 1.06 (s, 9H).

Step B:2-[(2S)-4-[2-[[(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.NH₃ was bubbled in methanol (50 mL) at −60° C. for 0.5 h. To the mixturewas added benzyl(2S)-4-[2-[[(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(0.90 g, 1.02 mmol, 1.00 eq) and Pd/C (0.10 g, 10.0% purity). Afterstirred at 20° C. for 1 hour under H: at 15 psi, the mixture wasfiltered and concentrated under vacuum to give2-[(2S)-4-[2-[[(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(763 mg, crude) as a yellow oil and used into next step without furtherpurification. LCMS [ESI, M+1]: 752.

Step C:2-[(2S)-4-[2-[[(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of 2-[(2S)-4-[2-[[(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(0.76 g, crude) and Et₃N (511 mg, 5.05 mmol, 703 uL) in dichloromethane(5.00 mL) was added prop-2-enoyl prop-2-enoate (127 mg, 1.01 mmol) at−40° C. After stirred at 20° C. for 1 hour, the mixture was quenchedwith saturated sodium bicarbonate (0.20 mL) and concentrated undervacuum. The residue was purified by column chromatography (Al₂O₃,methanol/ethyl acetate=1/10) to give2-[(2S)-4-[2-[[(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(0.50 g, 552 umol, two steps 55% yield) as a yellow oil. LCMS [ESI,M+1]: 806.

¹H NMR (400 MHz, chloroform-d) δ=8.25-8.17 (m, 1H), 7.90-7.82 (m, 1H),7.68-7.58 (m, 5H), 7.50 (td, J=2.4, 5.2 Hz, 2H), 7.46-7.35 (m, 7H), 7.14(d, J=7.6 Hz, 1H), 6.67-6.51 (m, 1H), 6.46-6.31 (m, 1H), 5.83 (br d,J=10.8 Hz, 1H), 5.08 (br s, 1H), 4.43-4.31 (m, 2H), 4.27 (br s, 2H),4.16-4.00 (m, 4H), 3.67-3.55 (m, 1H), 3.46 (br s, 1H), 3.31 (br dd,J=8.4, 14.4 Hz, 2H), 3.17 (br dd, J=6.0, 9.6 Hz, 1H), 3.11-2.73 (m, 6H),2.47 (s, 3H), 2.42 (br dd, J=6.0, 9.6 Hz, 1H), 2.11 (tt, J=4.0, 8.4 Hz,1H), 1.96-1.84 (m, 1H), 1.06 (s, 9H).

Step D:2-[(2S)-4-[2-[[(2S,4R)-4-hydroxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.A mixture of2-[(2S)-4-[2-[[(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(0.40 g, 496 umol, 1.00 eq), KF (57.7 mg, 902 umol, 23.3 uL, 2.00 eq)and 18-crown-6 (262 mg, 992 umol, 2.00 eq) in THF (10.0 mL) was stirredat 30° C. for 24 hours. The mixture was concentrated under vacuum. Theresidue was purified by reversed phase flash [water (TFA,0.10%)/acetonitrile]. The desired fractions were adjust pH>7 bysaturated sodium bicarbonate (200 mL) and extracted with ethyl acetate(3×30.0 mL). The organic layers were dried over Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified prep-HPLC (column:Phenomenex Gemini 150*25 mm*10 um; mobile phase: [water (0.05% ammoniahydroxide v/v)-ACN], B %: 37%-67%, 12 min). The desired fractions wereconcentrated and lyophilized to give title compound2-[(2S)-4-[2-[[(2S,4R)-4-hydroxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(I-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 315, 51.5 mg, 90.7 umol, 18% yield, 96.3% purity) as a whitesolid. LCMS [ESI, M+1]: 568.

SFC: “AS-3S_3_5_40_3 ML Column: Chiralpak AS-3 100×4.6 mm I.D., 3 umMobile phase: methanol (0.05%, DEA) in CO₂ from 5% to 40% Flow rate: 3mL/min Wavelength: 220 nm”.

¹H NMR (400 MHz, chloroform-d) δ=8.26-8.17 (m, 1H), 7.91-7.83 (m, 1H),7.61 (d, J=8.0 Hz, 1H), 7.55-7.48 (m, 2H), 7.44 (t, J=8.0 Hz, 1H), 7.15(d, J=7.2 Hz, 1H), 6.59 (br s, 1H), 6.47-6.36 (m, 1H), 5.84 (br d,J=10.8 Hz, 1H), 5.11 (br s, 1H), 4.52-4.43 (m, 1H), 4.39 (dd, J=4.8,10.8 Hz, 1H), 4.34-4.20 (m, 3H), 4.15 (br d, J=14.0 Hz, 1H), 4.02 (br d,J=12.0 Hz, 2H), 3.61 (br s, 1H), 3.53-3.41 (m, 2H), 3.34 (br s, 2H),3.12 (br s, 1H), 3.05-2.89 (m, 3H), 2.88-2.66 (m, 2H), 2.50 (s, 3H),2.34 (dd, J=5.6, 10.0 Hz, 1H), 2.16-1.94 (m, 2H).

Example 316

2-((S)-1-acryloyl-4-(7-(4-fluoronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: benzyl(2S)-2-(cyanomethyl)-4-[7-(4-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(Intermediate 65, 1.0 g, 1.98 mmol, 1.0 eq) and1-bromo-4-fluoro-naphthalene (2.23 g, 9.89 mmol, 5.0 eq) in toluene(20.0 mL) was added Cs₂CO₃ (1.93 g, 5.93 mmol, 3.0 eq), XPhos-Pd-G3 (335mg, 396 umol, 0.2 eq), the reaction mixture was stirred at 70° C. for 24hours under N₂. After completion, the reaction was added water (20.0mL), extracted with EA (2×20.0 mL), the organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=3/1 to Ethylacetate:Methanol=20:1) to give benzyl(2S)-2-(cyanomethyl)-4-[7-(4-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(680 mg, 957 umol, 48% yield, 91.4% purity) as white solid. LCMS [ESI,M+1]: 650.

Step B:2-[(2S)-4-[7-(4-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[7-(4-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(650 mg, 1.0 mmol, 1.0 eq) in MeOH (15 mL) was added NH₃·MeOH (1.0 mmol,15.0 mL, 1.0 eq) and Pd/C (500 mg, 10% purity), the suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred under H₂ (15 Psi) at 20° C. for 0.5 hour. After completion, thereaction was filtered through a Celite, and the filtrate wasconcentrated to give2-[(2S)-4-[7-(4-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(460 mg, 824 umol, 82% yield, 92.4% purity) as white solid which wasused for the next step without further purification. LCMS [ESI, M+1]:516.

Step C:2-[(2S)-4-[7-(4-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a mixture of2-[(2S)-4-[7-(4-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(460 mg, 892 umol, 1.0 eq) in DCM (10 mL) was added DIEA (461 mg, 3.57mmol, 622 uL, 4.0 eq) and prop-2-enoyl prop-2-enoate (113 mg, 892 umol,1.0 eq) at 0° C., the reaction mixture was stirred at 20° C. for 0.5hour. After completion, the reaction mixture was quenched with MeOH (5.0mL), and concentrated. The residue was purified by prep-HPLC((Phenomenex Gemini 150*25 mm*10 um; mobile phase: [water (0.05% ammoniahydroxide v/v)-ACN]; B %: 53%-83%, 12 min), the obtained product wasconcentrated and then under lyophilization. The title compound2-[(2S)-4-[7-(4-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 316, 100 mg, 175 umol, 20% yield, 100% purity) was obtained aswhite solid. LCMS [ESI, M+1]: 570.

¹H NMR (400 MHz, chloroform-d) δ 8.28-8.22 (m, 1H), 8.17-8.10 (m, 1H),7.63-7.55 (m, 2H), 7.14-7.05 (m, 2H), 6.70-6.55 (m, 1H), 6.42 (dd,J=1.6, 16.8 Hz, 1H), 5.86 (br d, J=10.4 Hz, 1H), 5.20-4.48 (m, 1H), 4.41(dd, J=4.8, 10.4 Hz, 1H), 4.33-4.10 (m, 4H), 4.09-3.92 (m, 2H),3.78-3.20 (m, 4H), 3.19-3.07 (m, 2H), 3.05-2.64 (m, 5H), 2.50 (s, 3H),2.36-2.25 (m, 1H), 2.13-2.02 (m, 1H), 1.92-1.73 (m, 3H).

Example 317

2-((S)-1-acryloyl-4-(7-(3-hydroxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: tert-butyl(2S)-2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a mixture of tert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(Intermediate 66, 880 mg, 1.87 mmol, 1.0 eq) and(4-bromo-2-naphthyl)2,2-dimethylpropanoate (Intermediate 54, 745 mg,2.43 mmol, 1.3 eq) in toluene (20.0 mL) was added Cs₂CO₃ (1.22 g, 3.73mmol, 2.0 eq), RuPhos (174 mg, 373 umol, 0.2 eq) and Pd₂(dba)₃ (171 mg,187 umol, 0.1 eq), the mixture was stirred at 90° C. for 12 hours underN₂. After completion, the reaction mixture was added water (30 mL), thenextracted with EA (2×20 mL), the combined organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=3/1 to Ethylacetate: Methanol=20/1) to give tert-butyl(2S)-2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(750 mg, 774 umol, 41% yield, 72.9% purity) as brown solid. LCMS [ESI,M+1]: 698.

Step B:[4-[4-[(3S)-3-(cyanomethyl)piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate.To a solution of tert-butyl(2S)-2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(750 mg, 774 umol, 1.0 eq) in DCM (5.0 mL) was added TFA (7.70 g, 67.5mmol, 5.0 mL, 87.3 eq), the reaction mixture was stirred at 20° C. for 1hour. After completion, the reaction was concentrated to give[4-[4-[(3S)-3-(cyanomethyl)piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (550 mg, crude, TFA) as brown oil which was usedfor the next step without further purification. LCMS [ESI, M+1]: 598.

Step C:[4-[4-[(3S)-3-(cyanomethyl-4-prop-2-enoyl-piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate.To a mixture of[4-[4-[(3S)-3-(cyanomethyl)piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate(550 mg, 773 umol, 1.0 eq, TFA) in DCM (5 mL) was added TEA (469 mg,4.64 mmol, 645 uL, 6.0 eq) and prop-2-enoyl prop-2-enoate (97.5 mg, 773umol, 1.0 eq) at 0° C., the reaction mixture was stirred at 20° C. for0.5 hour. After completion, the reaction mixture was quenched with MeOH(5.0 mL), and concentrated. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate-3/1 to Ethylacetate/Methanol-10/1) to give[4-[4-[(3S)-3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate(270 mg, 323 umol, 42% yield, 78.2% purity) as yellow solid. LCMS [ESI,M+1]: 652.

Step D:2-[(2S)-4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a mixture of[4-[4-[(3S)-3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate(270 mg, 323 umol, 1.0 eq) in THF (2.0 mL) was added a solution of NaOH(38.8 mg, 969 umol, 3.0 eq) in H₂O (2.0 mL), the reaction mixture wasstirred at 20° C. for 4 hours. After completion, the reaction mixturewas added water (10 mL), then extracted with EA (2×10 mL), the combinedorganic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by prep-HPLC (column: Phenomenex Luna Phenyl-Hexyl150_30_5 um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 35%-62%, 3 min), the obtained product was concentrated, and thenunder lyophilization. The title compound2-[(2S)-4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 317, 26.6 mg, 46.3 umol, 14% yield, 98.8% purity) was obtainedas pink solid. LCMS [ESI, M+1]: 568.

¹H NMR (400 MHz, chloroform-d) δ 8.01-7.93 (m, 1H), 7.64 (br d, J=8.4Hz, 1H), 7.41 (br t, J=7.2 Hz, 1H), 7.33-7.29 (m, 2H), 6.88 (s, 1H),6.66-6.50 (m, 2H), 6.39 (br d, J=16.4 Hz, 1H), 5.84 (br d, J=10.8 Hz,1H), 5.04-4.89 (br s, 1H), 4.64-4.49 (m, 1H), 4.32-4.21 (m, 1H), 4.11(br s, 2H), 4.00 (br d, J=14.0 Hz, 1H), 3.94-3.71 (m, 2H), 3.47-3.08 (m,4H), 2.93-2.61 (m, 10H), 2.47-2.33 (m, 1H), 2.25-2.06 (m, 1H), 2.00-1.89(m, 3H).

Example 318

2-[(2S)-4-[7-(4-fluoro-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: tert-butyl4-[(3S)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate.To a solution of tert-butyl 4-[(3S)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(Intermediate 64, 500 mg, 901 umol, 1.00 eq) and[(2R)-1-methylpyrrolidin-2-yl]methanol (208 mg, 1.80 mmol, 2.00 eq) intoluene (10.0 mL) was added t-BuONa (173 mg, 1.80 mmol, 2.00 eq). Themixture was stirred at 0° C. for 10 minutes. Upon completion, themixture was diluted with water (5 mL) and extracted with EtOAc (2×30mL). The organic layers were dried over Na₂SO₄ and concentrated undervacuum. The residue was purified by reversed-phase flash [water (0.1%FA)/acetonitrile]. The pH was adjusted to 7 with saturated sodiumbicarbonate solution and the mixture was extracted with ethyl acetate(2×30 mL). The organic layers were dried over Na₂SO₄ and concentratedunder vacuum to give tert-butyl4-[(3S)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(340 mg, 505 umol, 56% yield, 90.0% purity) as a yellow solid.

¹H NMR (400 MHz, chloroform-d) δ=7.45-7.32 (m, 5H), 5.28-5.12 (m, 2H),4.70-4.55 (m, 2H), 4.42-4.29 (m, 2H), 4.15-3.93 (m, 3H), 3.90-3.75 (m,2H), 3.43-3.16 (m, 3H), 3.09 (br t, J=7.6 Hz, 1H), 2.98 (dt, J=3.6, 12.4Hz, 1H), 2.89-2.54 (m, 5H), 2.47 (s, 3H), 2.33-2.22 (m, 1H), 2.05-1.96(m, 1H), 1.90-1.74 (m, 3H), 1.49 (s, 9H).

Step B: benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of tert-butyl 4-[(3S)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(340 mg, 561 umol, 1.00 eq) in dioxane (4.00 mL) was added HCl/dioxane(4 M, 4.00 mL) at 0° C. The mixture was stirred at 25° C. for 1 hour.Upon completion, the mixture was concentrated under vacuum. The pH wasadjusted to 8 with saturated sodium bicarbonate aqueous solution and themixture was extracted with the mixed solvent (DCM/i-PrOH 2/1, 2×9 mL).The organic layers were dried over Na₂SO₄ and concentrated under vacuumto give benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(255 mg, 444 umol, 79% yield, 88.0% purity) as a yellow solid which wasused directly in the next step without further purification. LCMS [ESI,M+1]: 506.

Step C: benzyl(2S)-2-(cyanomethyl)-4-[7-(4-fluoro-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.Benzyl (2S)-2-(cyanomethyl)-4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(210 mg, 366 umol, 1.00 eq), 1-bromo-4-fluoro-naphthalene (247 mg, 1.10mmol, 3.00 eq), RuPhos (68.2 mg, 146 umol, 0.40 eq), t-BuONa (87.8 mg,914 umol, 2.50 eq) and Pd₂(dba)₃ (66.9 mg, 73.1 umol, 0.20 eq) intoluene (2.00 mL) was de-gassed and then heated to 90° C. for 15 hoursunder N₂. Upon completion, the mixture was concentrated under vacuum,diluted with water (3 mL) and extracted with EtOAc (2×10 mL). Theorganic layers were dried over Na₂SO₄ and concentrated under vacuum. Theresidue was purified by reversed-phase flash [water (0.1%FA)/acetonitrile]. The mixture was neutralized with saturated sodiumbicarbonate solution, concentrated under vacuum to remove MeCN andextracted with ethyl acetate (3×30 mL). The organic layers were driedover Na₂SO₄ and concentrated under vacuum to give benzyl(2S)-2-(cyanomethyl)-4-[7-(4-fluoro-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(120 mg, 175 umol, 48% yield, 95.0% purity) as a yellow oil.

¹H NMR (400 MHz, chloroform-d) δ=8.23 (dd, J=2.0, 4.4 Hz, 1H), 8.16-8.08(m, 1H), 7.60-7.52 (m, 2H), 7.44-7.33 (m, 5H), 7.14-7.02 (m, 2H),5.28-5.16 (m, 2H), 4.69 (br s, 1H), 4.39 (dd, J=4.8, 10.8 Hz, 1H),4.29-4.14 (m, 4H), 4.07 (br s, 1H), 3.95 (br d, J=12.4 Hz, 1H),3.54-3.15 (m, 4H), 3.14-3.03 (m, 2H), 3.00-2.61 (m, 5H), 2.48 (s, 3H),2.35-2.23 (m, 1H), 1.97-2.05 (m, 1H), 1.92-1.83 (m, 3H).

Step D:2-[(2S)-4-[7-(4-fluoro-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.NH₃ was bubbled into MeOH (5.00 mL) for 3 minutes at −40° C. To thesolution was added a solution of benzyl(2S)-2-(cyanomethyl)-4-[7-(4-fluoro-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(120 mg, 185 umol, 1.00 eq) in MeOH (5.00 mL) and Pd/C (60.0 mg, 10%purity) under N₂. The suspension was degassed under vacuum and purgedwith H₂ several times. The reaction was stirred under H₂ (15 psi) at 25°C. for 1 hour. Upon completion, the reaction mixture was filtered andthe filtrate was concentrated to give2-[(2S)-4-[7-(4-fluoro-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(80.0 mg, 147 umol, 79% yield, 94.6% purity) as a yellow solid which wasused directly in the next step without further purification. LCMS [ESI,M+1]: 516.

Step E:2-[(2S)-4-[7-(4-fluoro-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(4-fluoro-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(80.0 mg, 155 umol, 1.00 eq) and TEA (78.5 mg, 776 umol, 108 uL, 5.00eq) in DCM (2.00 mL) was added prop-2-enoyl prop-2-enoate (19.6 mg, 155umol, 1.00 eq) dropwise at 0° C. The mixture was stirred at 25° C. for 1hour. Upon completion, the reaction was quenched with MeOH (0.5 mL),diluted with water (2 mL) and extracted with EtOAc (2×5 mL). The organiclayers were dried over Na₂SO₄ and concentrated under vacuum. The residuewas purified by prep-TLC (EtOAc/MeOH 7/1) and prep-HPLC (column:Phenomenex Gemini 150*25 mm*10 um; mobile phase: [water (0.05% ammoniahydroxide v/v)-ACN]; B %: 52%-82%, 12 min). The desired fractions werecollected and lyophilized to give title compound2-[(2S)-4-[7-(4-fluoro-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 318, 21.0 mg, 36.7 umol, 24% yield, 99.8% purity) as a whitesolid. LCMS [ESI, M+1]: 570.

SFC condition: OD-3S_3_40_3 ML Column: Chiralcel OD-3 100×4.6 mm I.D., 3um Mobile phase: 40% methanol (0.05% DEA) in CO₂. Flow rate: 3 mL/min,Wavelength: 220 nm.

¹H NMR (400 MHz, chloroform-d) δ=8.33-8.22 (m, 1H), 8.16-8.08 (m, 1H),7.62-7.52 (m, 2H), 7.14-7.02 (m, 2H), 6.59 (br s, 1H), 6.46-6.36 (m,1H), 5.84 (br d, J=10.4 Hz, 1H), 5.10 (br s, 1H), 4.87-4.33 (m, 2H),4.30-4.10 (m, 4H), 4.09-3.78 (m, 2H), 3.77-3.23 (m, 2H), 3.22-2.53 (m,5H), 2.48 (s, 3H), 2.34-2.23 (m, 1H), 2.13-2.00 (m, 1H), 1.92-1.76 (m,3H).

Example 319

2-((S)-1-acryloyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-(((R)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: benzyl4-[(3S)-4-tert-butoxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate.To a solution of [(2R)-1-methylpyrrolidin-2-yl]methanol (1.31 g, 11.4mmol, 3 eq) in THF (10 mL) was added NaH (304 mg, 7.59 mmol, 60% purityin mineral oil, 2 eq) at 0° C., the mixture was stirred at 0° C. for 0.5hour. Benzyl4-[(3S)-4-tert-butoxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(2 g, 3.79 mmol, 1 eq) was added into the mixture and the mixture wasstirred at 80° C. for 3 hours. The reaction mixture was quenched withice water (20 mL) and extracted with ethyl acetate (50 mL×3). Thecombined organic layers were washed with brine (20 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by reversed phase flash [water (0.1%formic acid)/acetonitrile)]. The desired fractions were collected andadjusted pH=7 with saturated NaHCO₃ aqueous solution and extracted withethyl acetate (30 mL×3). The combined organic layers were washed withbrine (20 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure. Benzyl4-[(3S)-4-tert-butoxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(1 g, 1.60 mmol, 42% yield, 97% purity) was obtained as a yellow oil.LCMS [ESI, M+1]: 606.

¹H NMR (400 MHz, chloroform-d) δ=7.43-7.31 (m, 5H), 5.19 (s, 2H),4.75-4.64 (m, 1H), 4.59 (br s, 1H), 4.44 (d, J=18.8 Hz, 1H), 4.35 (br s,1H), 4.21-4.11 (m, 1H), 4.07-3.64 (m, 4H), 3.43 (br s, 1H), 3.30-3.15(m, 2H), 3.10 (br t, J=7.6 Hz, 1H), 3.03-2.91 (m, 1H), 2.83-2.55 (m,5H), 2.53-2.42 (m, 3H), 2.35-2.22 (m, 1H), 2.11-2.01 (m, 1H), 1.88-1.74(m, 3H), 1.51 (s, 9H).

Step B: tert-Butyl(2S)-2-(cyanomethyl)-4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.NH₃ was bubbled in MeOH (100 mL) at −60° C. for 30 minutes. To asolution of benzyl4-[(3S)-4-tert-butoxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(900 mg, 1.49 mmol, 1 eq) in above mixture was added dry Pd/C (500 mg,10% purity) under N₂. The suspension was degassed under vacuum andpurged with H₂ several times. The mixture was stirred under H₂ (15 psi)at 25° C. for 1 hour. The mixture was concentrated under vacuum. Theresidue was purified by reversed phase flash [water (0.1% formicacid)/acetonitrile)]. The mixture was adjusted pH=7 with saturatedNaHCO₃ aqueous solution and extracted with ethyl acetate (20 mL×3). Thecombined organic layers were washed with brine (20 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give theproduct. tert-Butyl(2S)-2-(cyanomethyl)-4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(650 mg, 1.24 mmol, 84% yield, 90% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 472.

Step C: tert-Butyl(2S)-4-[7-[3-chloro-2-(trifluoromethyl]phenyl-2-[[(2R)-1-methylpyrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.A mixture of 1-bromo-3-chloro-2-(trifluoromethyl)benzene (1.32 g, 5.09mmol, 4 eq), tert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(600 mg, 1.27 mmol, 1 eq), Cs₂CO₃ (1.04 g, 3.18 mmol, 2.5 eq), Pd₂(dba)₃(233 mg, 254 umol, 0.2 eq) and RuPhos (118 mg, 254 umol, 0.2 eq) intoluene (10 mL) was degassed and purged with N₂ for 3 times, and thenthe mixture was stirred at 90° C. for 3 hours under N₂ atmosphere. Thereaction mixture was diluted with water (20 mL) and extracted with ethylacetate (50 mL×3). The combined organic layers were washed with brine(30 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue. The residue was purified by columnchromatography (SiO₂, Ethyl acetate/MeOH=100/1 to 10:1) and furtherpurified by reversed phase flash [water (0.1% formicacid)/acetonitrile)]. The mixture was adjusted PH=7 with saturatedNaHCO₃ aqueous solution and extracted with ethyl acetate (20 mL×3). Thecombined organic layers were washed with brine (20 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give theproduct. tert-Butyl(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(370 mg, 569 umol, 45% yield, 100% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 650

¹H NMR (400 MHz, chloroform-d) δ=7.40 (t, J=8.0 Hz, 1H), 7.30-7.24 (m,1H), 7.19 (d, J=8.4 Hz, 1H), 4.61 (br s, 1H), 4.40 (br s, 1H), 4.24-4.14(m, 1H), 4.13-3.98 (m, 4H), 3.95-3.80 (m, 1H), 3.39-2.95 (m, 6H),2.93-2.62 (m, 5H), 2.52 (br s, 3H), 2.32 (br s, 1H), 2.14-2.05 (m, 1H),1.85-1.71 (m, 3H), 1.52 (s, 9H).

Step D:2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl (2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(370 mg, 569 umol, 1 eq) in DCM (700 uL) was added TFA (973 mg, 8.54mmol, 632 uL, 15 eq). The mixture was stirred at 25° C. for 1 hour. Themixture was concentrated under vacuum. Compound2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(377 mg, 567 umol, 99% yield, TFA) was obtained as a yellow oil and usedto next step directly without purification. LCMS [ESI, M+1]: 550.

Step E:2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrid[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of 2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(377 mg, 567 umol, 1 eq, TFA) in DCM (5 mL) was added TEA (574 mg, 5.68mmol, 790 uL, 10 eq) at 0° C. After addition, the prop-2-enoylprop-2-enoate (57.3 mg, 454 umol, 0.8 eq) in DCM (1 mL) was addeddropwise at 0° C. After stirred at 25° C. for 1 hour, the reactionmixture was quenched with saturated NaHCO₃ aqueous solution (1 mL). Thendiluted with water (20 mL) and extracted with ethyl acetate (20 mL×3).The combined organic layers were washed with brine (20 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (Al₂O₃,EA/MeOH=100/1 to 10:1) and further purified by prep-HPLC (column:Phenomenex Gemini 150*25 mm*10 um; mobile phase: [water (0.05% ammoniahydroxide v/v)-ACN]; B %: 50%-80%, 12 min). Title compound2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 319, 95 mg, 154 umol, 27% yield, 98% purity) was obtained as awhite solid after lyophilisation. LCMS [ESI, M+1]: 604.

SFC condition: “OD-3S_3_5_40_3 ML Column: Chiralcel OD-3 100×4.6 mmI.D., 3 um Mobile phase: methanol (0.05% DEA) in CO₂ from 5% to 40% Flowrate: 3 mL/min Wavelength: 220 nm”.

¹H NMR (400 MHz, chloroform-d) δ=7.40 (d, J=8.0 Hz, 1H), 7.29-7.25 (m,1H), 7.19 (d, J=8.0 Hz, 1H), 6.71-6.51 (m, 1H), 6.45-6.34 (m, 1H), 5.83(d, J=10.4 Hz, 1H), 5.25-4.52 (m, 1H), 4.38 (dd, J=4.8, 10.4 Hz, 1H),4.22-4.04 (m, 4H), 3.96 (br d, J=11.6 Hz, 2H), 3.74-3.02 (m, 5H),2.99-2.61 (m, 6H), 2.48 (s, 3H), 2.35-2.23 (m, 1H), 2.14-1.97 (m, 1H),1.92-1.79 (m, 3H).

Example 320

2-[(2S)-4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

Step A:benzyl(2S)-2-(cyanomethyl)-4-[2[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a mixture of benzyl(2S)-2-(cyanomethyl)-4-[2-methylsulfinyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(Intermediate 64, 300 mg, 517 umol, 1.0 eq),[(2S)-1-isopropylpyrrolidin-2-yl]methanol (148 mg, 1.03 mmol, 2.0 eq) intoluene (15.0 mL) was added t-BuONa (99.3 mg, 1.03 mmol, 2.0 eq) inportions at 0° C., the reaction mixture was degassed and purged with N₂for 3 times, and then the mixture was stirred at 0° C. for 30 min underN₂ atmosphere. After completion, the organic solvent was washed withwater (10.0 mL). The aqueous phase was extracted with ethyl acetate(3×20.0 mL). Combined extracts were washed with brine (50.0 mL), driedwith Na₂SO₄, the solvent was then removed under vacuum. The residue waspurified by reversed phase flash (C18, 0.1% FA in water, 0-60% MeCN).The obtained product was adjusted with saturated NaHCO₃ aqueous to pH˜8and then concentrated, the aqueous was extracted with ethyl acetate(3×20.0 mL) and the combined organic layer was dried over Na₂SO₄,filtered and concentrated. Compoundbenzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(180 mg, 272 umol, 53% yield, 99.7% purity) was obtained as a whitesolid. LCMS [ESI, M+1]: 660.

Step B:2-[(2S)-4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.NH₃ was bubbled into methanol (20.0 mL) at −60° C. for 30 minutes.Benzyl (2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(130 mg, 197 umol, 1.0 eq) and Pd/C (80.0 mg, 197 umol, 10% purity, 1.0eq) was added to the above mixture, then the mixture was degassed andpurged with 112 for 3 times, and then the mixture was stirred at 25° C.for 1 hour under H₂ atmosphere. After completion, the crude mixture wasfiltered through a pad of celite. The cake was washed with methanol(30.0 mL) and the filtrate was dried under high vacuum. Compound2-[(2S)-4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(75.0 mg, 132 umol, 67% yield, 92.6% purity) was obtained as a graysolid. LCMS [ESI, M+1]: 526.

Step C:2-[(2S)-4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido-[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(100 mg, 190 umol, 1.0 eq) in DCM (5.00 mL) was added DIEA (73.8 mg, 571umol, 99.4 uL, 3.0 eq) and dropwise added prop-2-enoyl prop-2-enoate(36.0 mg, 285 umol, 1.50 eq) at 0° C. under N₂ atmosphere. The mixturewas stirred at 0° C. for 1 hour. After completion, the reaction wasquenched with water (10.0 mL). The crude mixture was extracted withethyl acetate (3×15.0 mL). Combined extracts were washed with brine(30.0 mL), the combined organic layer was dried over Na₂SO₄, filteredand concentrated under reduced pressure to give a residue. The residuewas purified by prep-HPLC (column. Phenomenex Luna Phenyl-Hexyl 150_30_5um; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B %: 52%-82%, 3 min) andlyophilization. Title compound2-[(2S)-4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 320, 21.3 mg, 36.1 umol, 19% yield, 98.1% purity) was obtainedas a yellow solid. LCMS [ESI, M+1]: 580.

¹H NMR (400 MHz, chloroform-d) δ 8.24-8.21 (m, 1H), 7.89-7.87 (m, 1H),7.63 (d, J=8.0 Hz, 1H), 7.54-7.50 (m, 2H), 7.45 (t, J=7.8 Hz, 1H), 7.16(d, J=7.2 Hz, 1H), 6.65-6.57 (m, 1H), 6.42 (dd, J=1.8, 16.8 Hz, 1H),5.86 (d, J=10.0 Hz, 1H), 5.16-4.51 (m, 1H), 4.35-4.22 (m, 3H), 4.15-3.95(m, 4H), 3.68-3.47 (m, 1H), 3.42-2.77 (m, 1H), 2.58-2.52 (m, 1H),1.90-1.75 (m, 3H), 1.17 (d, J=6.4 Hz, 3H), 1.10 (d, J=6.4 Hz, 3H).

Example 321

1-[(3S)-4-[7-(2-fluoro-6-hydroxy-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-methyl-piperazin-1-yl]prop-2-en-1-one

Step A: tert-butyl(3S)-4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-3-methyl-piperazine-1-carboxylate.The solution of7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (2 g, 6.80mmol, 1 eq), tert-butyl (3S)-3-methylpiperazine-1-carboxylate (1.50 g,7.4 mmol, 1.1 eq), DIEA (1.76 g, 13.6 mmol, 2.37 mL, 2 eq) in NMP (40mL) was stirred at 100° C. for 7 hours. Water (80 mL) was added into themixture. The resulting mixture was diluted with EtOAc (20 mL) andextracted with EtOAc (3×80 mL). The combined organic layers were washedwith brine (40 mL). The combined organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixturewas filtered and the filter cake was washed with EtOAc (3×5 mL). Thefiltrate was concentrated under vacuum. The residue was triturated with(PE:EtOAc=3:1, 20 mL) and filtered and the filter cake was washed with(PE:EtOAc=3:1, 40 mL). Compound tert-butyl(3S)-4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-3-methyl-piperazine-1-carboxylate(1.44 g, 3.14 mmol, 46.2% yield) was obtained as a white solid. LCMS[ESI, M+1]: 458.

¹H NMR (400 MHz, chloroform-d) δ=7.39-7.28 (m, 5H), 4.29-4.20 (m, 0.1),4.16-3.81 (m, 2H), 3.76 (br s, 1H), 3.73 (br s, 1H), 3.68 (s, 2H), 3.61(d, J=10.4 Hz, 2H), 3.37-3.28 (m, 1H), 3.11 (br s, 2H), 2.73-2.58 (m,4H), 1.48 (s, 9H), 1.23 (d, J=6.8 Hz, 3H).

Step B: tert-butyl(3S)-4-[7-benzyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate.To the solution of [(2S)-1-methylpyrrolidin-2-yl]methanol (830 mg, 7.21mmol, 855 uL, 2.5 eq) in THF (25 mL) was added NaH (230 mg, 5.76 mmol,60% purity, 2 eq) at 0° C. and stirred at 0° C. for 0.5 hour. Thentert-butyl(3S)-4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-3-methyl-piperazine-1-carboxylate(1.32 g, 2.88 mmol, 1 eq) was added to the mixture. The reaction mixturewas heated to 70° C. for 12 hours in a tube under N₂. The reactionmixture was quenched by water (10 mL). The resulting mixture was dilutedwith EtOAc (20 mL) and extracted with EtOAc (3×30 mL). The combinedorganic layers were washed with brine (30 mL). The combined organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by reversed phase flash column(ACN/Water (0.1% FA)=40%) to give tert-butyl(3S)-4-[7-benzyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate(1.35 g, 2.39 mmol, 82.9% yield, 95% purity) as a brown solid. LCMS[ESI, M+1]: 537.

¹H NMR (400 MHz, chloroform-d) δ=7.40-7.27 (m, 5H), 4.37 (br dd, J=5.2,10.8 Hz, 1H), 4.22-4.14 (m, 2H), 4.07-3.73 (m, 2H), 3.71-3.64 (m, 3H),3.63-3.49 (m, 2H), 3.34-3.24 (m, 1H), 3.21-2.92 (m, 3H), 2.79-2.64 (m,2H), 2.63-2.56 (m, 3H), 2.51 (s, 3H), 2.33 (br d, J=7.6 Hz, 1H),2.12-2.05 (m, 1H), 1.92-1.69 (m, 3H), 1.48 (s, 9H), 1.20 (d, J=6.8 Hz,3H).

Step C: tert-butyl(3S)-3-methyl-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To the solution of tert-butyl(3S)-4-[7-benzyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate(1.43 g, 2.66 mmol, 1 eq) in MeOH (28 mL) was added Pd(OH)₂/C (500 mg,10% purity) under N₂. The suspension was degassed under vacuum andpurged with H₂ several times. The mixture was stirred under H₂ (15 psi)at 40° C. for 4 hours. The reaction mixture was filtered, the filtercake was washed with MeOH (3×20 mL). The filtrate was concentrated undervacuum. The residue was purified by reversed phase flash column(ACN/Water (0.1% FA)=40%) to give tert-butyl(3S)-3-methyl-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(810 mg, 1.72 mmol, 64.7% yield, 95.0% purity) as a yellow solid. LCMS[ESI, M+1]: 447.

Step D: tert-butyl(3S)-4-[7-(2-fluoro-6-methoxy-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate.To the solution of tert-butyl(3S)-3-methyl-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 1.12 mmol, 1 eq), 2-bromo-1-fluoro-3-methoxy-benzene (459 mg,2.24 mmol, 2 eq) and t-BuONa (323 mg, 3.36 mmol, 3 eq) in toluene (10mL) was added BrettPhos-Pd-G3 (304 mg, 336 umol, 0.3 eq) under N₂. Thesuspension was degassed under vacuum and purged with N₂ several times.The mixture was stirred under N₂ at 90° C. for 16 hours. Water (10 mL)was added into the mixture. The resulting mixture was diluted with EtOAc(10 mL) and extracted with EtOAc (3×20 mL). The combined organic layerswere dried over anhydrous Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by silica gel chromatography (fromPE:EtOAc 2:1˜0:1 to EtOAc:MeOH 1:0˜5:1), then the residue purified byprep-HPLC (column. Phenomenex Synergi Max-RP 250*50 mm*10 um; mobilephase. [water (0.225% FA)-ACN]; B %: 32%-57%, 30; 80% min) to givetert-butyl(3S)-4-[7-(2-fluoro-6-methoxy-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate(180 mg, 300 umol, 26.8% yield, 95.0% purity) as a brown oil. LCMS [ESI,M+1]: 571.

¹H NMR (400 MHz, chloroform-d) δ=7.02 (dt, J=6.4, 8.4 Hz, 1H), 6.75-6.65(m, 2H), 4.36 (dd, J=4.8, 10.4 Hz, 1H), 4.27 (s, 2H), 4.24-4.17 (m, 1H),4.12-4.09 (m, 1H), 3.84 (s, 3H), 3.74-3.65 (m, 1H), 3.38-3.27 (m, 3H),3.24-2.94 (m, 3H), 2.67 (br d, J=4.4 Hz, 3H), 2.48 (s, 3H), 2.32-2.23(m, 1H), 2.08 (br d, J=3.2 Hz, 1H), 2.04-1.98 (m, 1H), 1.87-1.69 (m,4H), 1.49 (s, 9H), 1.25-1.21 (m, 3H).

Step E:7(2-fluoro-6-methoxy-phenyl)-4-[(2S)-2-methylpiperazin-1-yl]-2-[[(2S)-1-methylpyrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine.The solution of tert-butyl(3S)-4-[7-(2-fluoro-6-methoxy-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate(210 mg, 368 umol, 1 eq) and TFA (839 mg, 7.36 mmol, 545 uL, 20 eq) wasstirred at 25° C. for 0.5 hour. The reaction mixture was concentratedunder vacuum. Compound7-(2-fluoro-6-methoxy-phenyl)-4-[(2S)-2-methylpiperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(260 mg, crude, 2 TFA) was obtained as a yellow oil.

Step F:1-[(3S)-4-[7-(2-fluoro-6-methoxy-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-methyl-piperazin-1-yl]prop-2-en-1-one.To the solution of7-(2-fluoro-6-methoxy-phenyl)-4-[(2S)-2-methylpiperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(260 mg, crude, 2 TFA), DIEA (481 mg, 3.72 mmol, 648 uL,) in DCM (5 mL)was added prop-2-enoyl prop-2-enoate (46.9 mg, 372 umol) at 0° C., thenthe mixture was stirred at 25° C. for 1 hour. The reaction mixture wasquenched by water (1 mL). The resulting mixture was concentrated undervacuum. The residue was purified by reversed phase flash column(ACN/Water (0.1% FA)=33%) to give1-[(3S)-4-[7-(2-fluoro-6-methoxy-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-methyl-piperazin-1-yl]prop-2-en-1-one(130 mg, 235 umol, 63.2% yield, 95.0% purity) as a white solid. LCMS[ESI, M+1]: 525.

Step G:3-bromo-1-[(3S)-4-[7-(2-fluoro-6-hydroxy-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-methyl-piperazin-1-yl]propan-1-oneTo a solution of1-[(3S)-4-[7-(2-fluoro-6-methoxy-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-methyl-piperazin-1-yl]prop-2-en-1-one(80 mg, 152 umol, 1 eq) in PhBr (2 mL) was added BBr₃ (764 mg, 3.05mmol, 294 uL, 20 eq). The reaction mixture was stirred at 90° C. for 12hours. Upon completion, the reaction mixture was concentrated undervacuum. The residue was quenched with saturated NaHCO3 (2 mL) andextracted with EtOAc (2×20mL).3-bromo-1-[(3S)-4-[7-(2-fluoro-6-hydroxy-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-methyl-piperazin-1-yl]propan-1-one(90 mg, crude) was obtained as a brown oil. The crude product was usedfor next step without further purification.

Step H:1-[(3S)-4-[7(2-fluoro-6-hydroxy-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-methyl-piperazin-1-yl]prop-2-en-1-one.To a solution of3-bromo-1-[(3S)-4-[7-(2-fluoro-6-hydroxy-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-methyl-piperazin-1-yl]propan-1-one(90 mg, 152 umol, 1 eq) in THF (2 mL) was added TEA (154 mg, 1.52 mmol,212 uL, 10 eq). The reaction mixture was stirred at 20° C. for 12 hours.Upon completion, the reaction mixture concentrated under vacuum. Theresidue was purified by prep-TLC (DCM:MeOH=10:1) then prep-HPLC (column:Phenomenex Gemini 150*25 mm*10 um; mobile phase: [water (0.05% ammoniahydroxide v/v)-ACN]; B %: 48%-78%, 12 min) to give title compound1-[(3S)-4-[7-(2-fluoro-6-hydroxy-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-methyl-piperazin-1-yl]prop-2-en-1-one(EXAMPLE 321, 10.6 mg, 20.1 umol, 13% yield, 96.9% purity) was obtainedas a yellow solid. LCMS [ESI, M+1]: 511.

¹H NMR (400 MHz, Methanol-d₄) δ=7.17-6.97 (m, 1H), 6.93-6.76 (m, 1H),6.71 (d, J=8.4 Hz, 1H), 6.61 (dd, J=8.8, 11.2 Hz, 1H), 6.29 (br dd,J=4.8, 16.4 Hz, 1H), 5.82 (br d, J=10.8 Hz, 1H), 4.58-4.27 (m, 4H),4.20-4.04 (m, 3H), 4.03-3.87 (m, 1H), 3.68-3.39 (m, 2H), 3.30 (br s,2H), 3.25-3.05 (m, 2H), 2.82 (br s, 2H), 2.75 (td, J=6.8, 13.6 Hz, 1H),2.51 (s, 3H), 2.36 (q, J=9.2 Hz, 1H), 2.13-2.08 (m, 1H), 1.89-1.78 (m,2H), 1.77-1.67 (m, 1H), 1.28 (br d, J=5.2 Hz, 3H).

Example 322

2-(1-acryloyl-4-(2-(((S)-1-ethylpyrrolidin-2-yl)methoxy)-7-(4-fluoronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: benzyl2-(cyanomethyl)-4-[7-(4-fluoro-4-naphthyl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.benzyl2-(cyanomethyl)-4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(2.00 g, 4.56 mmol, 1.00 eq.), 1-bromo-4-fluoro-naphthalene (1.54 g,6.84 mmol, 1.50 eq.), Pd₂(dba)₃ (418 mg, 456 umol, 0.100 eq.), RuPhos(426 mg, 912 umol, 0.20 eq.) and cesium carbonate (4.46 g, 13.7 mmol,3.00 eq.) in toluene (40.0 mL) was de-gassed and then heated to 110° C.for 3 hours under N₂ atmosphere. The reaction mixture was quenched byaddition water (20.0 mL) at 20° C., then diluted with ethyl acetate (30mL) and extracted with ethyl acetate (20.0 mL×3). The combined organiclayers were washed with brine (50.0 mL), dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (SiO2,Petroleum ether/Ethyl acetate=1/1 to 0/1) to give benzyl2-(cyanomethyl)-4-[7-(4-fluoro-1-naphthyl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(2.00 g, 3.43 mmol, 75.2% yield) as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ=8.24 (dt, J=1.6, 4.8 Hz, 1H), 8.16-8.08 (m,1H), 7.64-7.53 (m, 2H), 7.47-7.34 (m, 5H), 7.15-7.03 (m, 2H), 5.22 (s,2H), 4.72 (brs, 1H), 4.29-4.17 (m, 2H), 4.12-4.04 (m, 1H), 3.95 (br d,J=12.0 Hz, 1H), 3.51-3.19 (m, 3H), 3.14-2.68 (m, 5H), 2.54 (s, 3H).

Step B: benzyl2-(cyanomethyl)-4-[7-(4-fluoro-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a mixture of benzyl2-(cyanomethyl)-4-[7-(4-fluoro-1-naphthyl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1.06 g, 1.82 mmol, 1.00 eq.) in ethyl acetate (33.0 mL) was addedm-CPBA (332 mg, 1.64 mmol, 85.0% purity, 0.90 eq.) in one portion at 20°C. under N₂ atmosphere. The mixture was stirred at 20° C. for 5 hours.The reaction was quenched by saturated sodium thiosulfate (20.0 mL) andthen extracted with ethyl acetate (20.0 mL×3), the combined organicphase was washed by brine (30.0 mL), concentrated to give benzyl2-(cyanomethyl)-4-[7-(4-fluoro-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1.00 g, 1.67 mmol, 91.8% yield) as a yellow solid which was used forthe next step without further purification. LCMS [M+1]: 599.1.

Step C: benzyl-2-(cyanomethyl)-4-[2-[[(2S)-1-ethylpyrrolidin-2-yl]methoxy]-7-(4-fluoro-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a mixture of benzyl2-(cyanomethyl)-4-[7-(4-fluoro-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 835.16 umol, 1.00 eq.) and[(2S)-1-ethylpyrrolidin-2-yl]methanol (216 mg, 1.67 mmol, 2.00 eq.) intoluene (10.0 mL) was added sodium tert-butoxide (120 mg, 1.25 mmol,1.50 eq.) in one portion at 0° C. under N₂ atmosphere. The mixture wasstirred at 0° C. for 30 min, The reaction mixture was quenched byaddition water (10.0 mL) at 0° C., and then diluted with ethyl acetate(10.0 mL) and extracted with ethyl acetate (10 mL×3). The combinedorganic layers were washed with brine (20.0 mL), dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure to givea residue which purified by Prep-HPLC (TFA condition) to givebenzyl-2-(cyanomethyl)-4-[2-[[(2S)-1-ethylpyrrolidin-2-yl]methoxy]-7-(4-fluoro-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 292 umol, 35.0% yield, 97.0% purity) as a colorless solid. LCMS[M+1]: 664.5.

Step D:2-[4-[2-[[(2S)-1-ethylpyrrolidin-2-yl]methoxy]-7-(4-fluoro-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.NH₃ (g) was bubbled into methanol (2 mL) for 5 min at 0° C., then addedinto a solution of benzyl2-(cyanomethyl)-4-[2-[[(2S)-1-ethylpyrrolidin-2-yl]methoxy]-7-(4-fluoro-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 301 umol, 1.00 eq.) in methanol (2.00 mL), then Pd/C (100 mg,10% purity) was added under N₂ atmosphere. The suspension was degassedunder vacuum and purged with H₂ several times. The mixture was stirredunder H₂ (15 psi) at 20° C. for 1 hours. Filtered and concentrated togive2-[4-[2-[[(2-S)-1-ethylpyrrolidin-2-yl]methoxy]-7-(4-fluoro-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(200 mg, crude) as a black solid which used for the next step withoutfurther purification. LCMS [M+1]: 530.5.

Step E:2-[4-[2-[[(2S)-1-ethylpyrrolidin-2-yl]methoxy]-7-(4-fluoro-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a mixture of2-[4-[2-[[(2S)-1-ethylpyrrolidin-2-yl]methoxy]-7-(4-fluoro-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(100 mg, 189 umol, 1.00 eq.) and DIEA (73.2 mg, 566 umol, 98.7 uL, 3.00eq.) in DCM (2.00 mL) was added prop-2-enoyl prop-2-enoate (47.6 mg, 378umol, 2.00 eq.) in DCM (1.00 mL) drop-wise at 0° C. under N₂ atmosphere.The mixture was stirred at 20° C. for 30 min, methanol (1.00 mL) wasadded the reaction mixture and then the solvent was removed to give aresidue which purified by Prep-TLC (SiO₂, DCM:MeOH=10:1, one drop ofNH₄OH was added) to give a crude product. Then by Prep-HPLC (basecondition) to give title compound2-[4-[2-[[(2S)-1-ethylpyrrolidin-2-yl]methoxy]-7-(4-fluoro-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(14.9 mg, 25.0 umol, 13.2% yield, 97.9% purity) as a white solid. LCMS[M+1]: 584.5.

¹H NMR (400 MHz, CDCl₃) δ=8.25 (dd, J=2.4, 4.8 Hz, 1H), 8.19-8.08 (m,1H), 7.63-7.54 (m, 2H), 7.15-7.03 (m, 2H), 6.61 (br s, 1H), 6.47-6.38(m, 1H), 5.86 (br d, J=10.2 Hz, 1H), 5.12 (br s, 1H), 4.38 (dd, J=4.4,10.6 Hz, 1H) 4.24 (br s, 2H), 4.20-4.10 (m, 2H), 4.04 (br d, J=12.0 Hz,2H), 3.76-2.67 (m, 12H), 2.52-2.37 (m, 1H), 2.32-2.21 (m, 1H), 2.09-1.97(m, 1H), 1.90-1.74 (m, 3H), 1.16 (t, J=7.2 Hz, 3H).

Example 323

2-[(2S)-4-[2-[[(2R,4S)-4-hydroxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: methyl (2R,4S)-4-hydroxy-1-methyl-pyrrolidine-2-carboxylate. Toa solution of methyl (2R,4S)-4-hydroxypyrrolidine-2-carboxylate (3 g,20.7 mmol, 1 eq, HCl) and formaldehyde (8.39 g, 103 mmol, 7.69 mL, 37%purity, 5 eq) in MeOH (30 mL) was added AcOH (1.24 g, 20.7 mmol, 1.18mL, 1 eq) at 15° C. After stirring for 30 minutes, NaBH₃CN (3.25 g, 51.7mmol, 2.5 eq) was added. The mixture was stirred for 16 hours. To themixture was added saturated aqueous sodium carbonate solution (50 mL),and then extracted with dichloromethane/methanol 10/1 (3×50 mL) Thecombined organic layers were dried over sodium sulfate, filtered andconcentrated under vacuum. Methyl(2R,4S)-4-hydroxy-1-methyl-pyrrolidine-2-carboxylate (2 g, 12.6 mmi, 61%yield) was obtained as a yellow oil.

Step B: methyl(2R,4S)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidine-2-carboxylate.To a solution of methyl(2R,4S)-4-hydroxy-1-methyl-pyrrolidine-2-carboxylate (1.70 g, 10.7 mmol,1.00 eq) in DMF (10.0 mL) was added imidazole (1.67 g, 24.6 mmol, 2.30eq) and tert-butylchlorodiphenylsilane (3.52 g, 12.8 mmol, 3.29 mL, 1.20eq). The mixture was stirred at 20° C. for 10 hours. The mixture wasdiluted with ethyl acetate (20.0 mL), washed with brine (3×30.0 mL),dried over Na₂SO₄, filtered and concentrated under vacuum. The residuewas purified by column chromatography (Al₂O₃, methanol/ethylacetate=1/10) to give methyl(2R,4S)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidine-2-carboxylate(3.00 g, 7.24 mmol, 68% yield) as a colorless oil. LCMS [ESI, M+1]: 398.

¹H NMR (400 MHz, chloroform-d) δ=7.63 (ddd, J=1.6, 3.6, 7.6 Hz, 4H),7.46-7.35 (m, 6H), 4.47-4.40 (m, 1H), 3.71 (s, 3H), 3.32 (t, J=8.4 Hz,1H), 3.25 (dd, J=6.0, 10.0 Hz, 1H), 2.42 (br d, J=5.2 Hz, 1H), 2.40 (s,3H), 2.18-2.01 (m, 2H), 1.07 (s, 9H).

Step C: [(2R,4S)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methanol. To a solution ofmethyl(2R,4S)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidine-2-carboxylate(1.50 g, 3.77 mmol, 1.00 eq) in THF (10.0 mL) was added LiAlH₄ (573 mg,15.1 mmol, 4.00 eq) at −40° C. After stirred at −40° C. for 1 hour, themixture was quenched with water (0.50 mL), NaOH solution (15.0%, 1.00mL), water (1.50 mL) The formed precipitate was filtered off and thefilter cake was washed with ethyl acetate (40.0 mL). The filtrate wasconcentrated under vacuum. The residue was purified by columnchromatography (Al₂O₃, methanol/ethyl acetate 1/10) to give[(2R,4S)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methanol (1.20 g, 3.18mmol, 84% yield) as a yellow oil. LCMS [ESI, M+1]: 370.

¹H NMR (400 MHz, chloroform-d) δ=7.67-7.62 (m, 4H), 7.46-7.36 (m, 6H),4.37-4.24 (m, 1H), 3.63 (dd, J=3.2, 11.2 Hz, 1H), 3.35 (dd, J=2.0, 10.8Hz, 1H), 3.15 (dd, J=6.0, 9.6 Hz, 1H), 2.76 (br t, J=8.0 Hz, 1H), 2.44(dd, J=6.0, 9.6 Hz, 1H), 2.33 (s, 3H), 2.04-1.85 (m, 2H), 1.06 (s, 9H).

Step D: benzyl(2S)-4-[2-[[2R,4S)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.To a solution of[(2R,4S)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methanol(305 mg, 827 umol, 1.20 eq) in THF (5.00 mL) was added t-BuONa (132 mg,1.38 mmol, 2.00 eq) at 0° C. followed by benzyl(2S)-2-(cyanomethyl)-4-[2-methylsulfinyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(Intermediate 64, 0.40 g, 689 umol, 1.00 eq). After stirring at 0° C.for 0.5 h, the mixture was diluted with ethyl acetate (30.0 mL), washedwith water (1×20.0 mL), dried over Na₂SO₄, filtered and concentratedunder vacuum. The residue was purified by column chromatography (Al₂O₃,petroleum ether/ethyl acetate=1/3) to give benzyl(2S)-4-[2-[[(2R,4S)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(0.35 g, 328 umol, 48% yield) as a yellow solid. LCMS [ESI, M/2+1]: 444.

¹H NMR (400 MHz, chloroform-d) δ=8.24-8.18 (m, 1H), 7.90-7.84 (m, 1H),7.69-7.59 (m, 5H), 7.52-7.48 (m, 2H), 7.44-7.36 (m, 12H), 7.14 (d, J=7.2Hz, 1H), 5.21 (s, 2H), 4.68 (br s, 1H), 4.42-4.36 (m, 1H), 4.32 (br dd,J=4.8, 10.4 Hz, 1H), 4.26 (br d, J=6.8 Hz, 2H), 4.17-4.06 (m, 3H),3.98-3.88 (m, 1H), 3.47 (br s, 1H), 3.29 (br d, J=10.8 Hz, 3H), 3.16 (brdd, J=6.0, 9.6 Hz, 1H), 3.11-2.95 (m, 3H), 2.91-2.73 (m, 3H), 2.47-2.36(m, 4H), 2.11 (ddd, J=4.8, 8.4, 13.2 Hz, 1H), 1.95-1.82 (m, 1H), 1.06(s, 9H).

Step E:2-[(2S)-4-[2-[[(2R,4S)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.NH₃ was bubbled in methanol (40.0 mL) at −78° C. for 0.5 h. Benzyl(2S)-4-[2-[[(2R,4S)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(0.32 g, 361 umol, 1.00 eq) and Pd/C (0.10 g, 10.0% purity) was addedinto the mixture. After stirring at 25° C. under H₂ at 15 psi for 1hour, the mixture was filtered and filtrate was concentrated undervacuum to give2-[(2S)-4-[2-[[(2R,4S)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(0.27 g, crude) as a yellow oil and used into next step without furtherpurification. LCMS [ESI, M/2+1]: 377.

Step F:2-[(2S)-4-[2-[[(2R,4S)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[(2V)-4-[2-[[(2R,4S)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(0.27 g, crude) and TEA (182 mg, 1.80 mmol, 250 uL) in dichloromethane(2.00 mL) was added prop-2-enoyl prop-2-enoate (45.3 mg, 359 umol) at 0°C. After stirring at 25° C. for 0.5 h, the mixture was quenched withmethanol (0.10 mL) and concentrated under vacuum. The residue waspurified by column chromatography (Al₂O₃, petroleum ether/ethylacetate=1/3) to give2-[(2S)-4-[2-[[(2R,4S)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(0.16 g, 171 umol, two steps 48% yield) as a yellow solid. LCMS [ESI,M+1]: 806.

Step G:2-[(2S)-4-[2-[[(2R,4S)-4-hydroxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.A mixture of2-[(2S)-4-[2-[[(2R,4S)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(0.16 g, 198 umol, 1.00 eq), KF (46.1 mg, 794 umol, 18.6 uL, 4.00 eq)and 18-crown-6 (210 mg, 794 umol, 4.00 eq) in THF (2.00 mL) was stirredat 40° C. for 12 hours. The mixture was concentrated under vacuum. Theresidue was purified by reversed phase flash [water (TFA,0.10%)/acetonitrile]. The desired fraction was collected and adjust pH>7by saturated sodium bicarbonate (2.00 mL) and then extracted with ethylacetate (3×30.0 mL), dried over Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by prep-HPLC (Phenomenex Gemini 150*25mm*10 um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %:38%-66%, 12 min). The desired fractions were collected and lyophilizedto give title compound2-[(2S)-4-[2-[[(2R,4S)-4-hydroxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 323, 36.3 mg, 63.9 umol, 32% yield, 98.1% purity) as a whitesolid. LCMS [ESI, M+1]: 568.

SFC: “OJ=3S_3_5_40_3 ML Column: Chiralcel OJ=3 100×4.6 mm I.D., 3 umMobile phase: methanol (0.05% DEA) in CO₂ from 5% to 40% Flow rate: 3mL/min Wavelength: 220 nm”.

¹H NMR (400 MHz, chloroform-d) δ=8.25-8.18 (m, 1H), 7.91-7.83 (m, 1H),7.62 (d, J=8.0 Hz, 1H), 7.55-7.48 (m, 2H), 7.44 (t, J=8.0 Hz, 1H), 7.15(d, J=7.2 Hz, 1H), 6.60 (br s, 1H), 6.46-6.35 (m, 1H), 5.84 (br d, J=9.6Hz, 1H), 5.20-4.53 (m, 1H), 4.47 (quin, J=5.6 Hz, 1H), 4.41 (dd, J=4.8,10.8 Hz, 1H), 4.34-4.19 (m, 3H), 4.14 (br d, J=13.2 Hz, 1H), 4.02 (br d,J=11.6 Hz, 2H), 3.63 (br s, 1H), 3.46 (br dd, J=6.0, 9.6 Hz, 2H), 3.36(br s, 2H), 3.12 (br s, 1H), 3.07-2.90 (m, 3H), 2.90-2.67 (m, 2H), 2.51(s, 3H), 2.35 (dd, J=5.2, 9.6 Hz, 1H), 2.14-2.04 (m, 1H), 2.04-1.96 (m,1H).

Example 324

2-[(2S)-4-[7-(3-methoxy-2-methyl-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5N-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: Benzyl(2S)-2-(cyanomethyl)-4-[7-(3-methoxy-2-methyl-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a mixture of benzyl (2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(Intermediate 65, 300 mg, 593 umol, 1.00 eq),1-bromo-3-methoxy-2-methylbenzene (239 mg, 1.19 mmol, 2 eq), Cs₂CO₃ (580mg, 1.78 mmol, 3 eq), Pd₂(dba)₃ (109 mg, 119 umol, 0.2 eq) and RuPhos(83.1 mg, 178 umol, 0.3 eq) in toluene (30 mL) was degassed and purgedwith N₂ for 3 times, and then the mixture was stirred at 90° C. for 16hours under N₂ atmosphere. To the reaction mixture was added H₂O (1×200mL) and Ethyl acetate (1×250 mL). The organic phase was separated,washed with brine (1×200 mL), dried over sodium sulfate, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by reversed phase flash [water (0.1% FA)/acetonitrile]. Thedesired fractions were collected and neutralized to pH=7 with saturatedNaHCO₃ solution and extracted with ethyl acetate (100 mL). The extractswere dried over sodium sulfate, filtered and concentrated under vacuum.Benzyl(2S)-2-(cyanomethyl)-4-[7-(3-methoxy-2-methyl-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4d]pyrimidin-4-yl]piperazine-1-carboxylate(170 mg, 270 umol, 45% yield, 99.2% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 626.

¹H NMR (400 MHz, chloroform-d) δ=7.43-7.33 (m, 5H), 7.16 (t, J=8.0 Hz,1H), 6.72 (d, J=8.0 Hz, 1H), 6.68 (d, J=8.0 Hz, 1H), 5.20 (s, 2H), 4.80(br dd, J=6.8, 11.6 Hz, 1H), 4.68 (br s, 1H), 4.45 (br dd, J=4.4, 12.0Hz, 1H), 4.21-4.08 (m, 3H), 4.05 (s, 2H), 3.94 (br d, J=12.8 Hz, 1H),3.85 (s, 3H), 3.67-3.56 (m, 1H), 3.32 (br d, J=11.2 Hz, 3H), 3.24-3.01(m, 3H), 2.95-2.67 (m, 8H), 2.32-2.10 (m, 5H), 2.00 (br s, 1H).

Step B:2-[(2S)-4-[7-(3-methoxy-2-methyl-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a mixture of benzyl(2S)-2-(cyanomethyl)-4-[7-(3-methoxy-2-methyl-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(260 mg, 416 umol, 1.00 eq), Pd/C (130 mg, 10% purity) and NH₃ in MeOH(50 mL) was degassed and purged with H₂ for 3 times, and then themixture was stirred at 25° C. for 1 hr under H₂ atmosphere at 15 psipressure. After that, the catalyst was filtered off and the filtrate wasconcentrated under vacuum. Compound2-[(2S)-4-[7-(3-methoxy-2-methyl-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(200 mg, 376 umol, 91% yield, 92.4% purity) was obtained as a yellowoil. LCMS [ESI, M+1]: 492.

Step C:2-[(2S)-4-[7-(3-methoxy-2-methyl-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a mixture of2-[(2S)-4-[7-(3-methoxy-2-methyl-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(200 mg, 407 umol, 1.00 eq) and TEA (206 mg, 2.03 mmol, 283 uL, 5.00 eq)in DCM (10 mL) was added prop-2-enoyl prop-2-enoate (41.0 mg, 325 umol,0.800 eq) at 0° C. The mixture was stirred at 25° C. for 1 hour. Thereaction mixture was quenched with NaHCO₃ saturated solution (5 mL) at0° C., and then extracted with CH₂Cl₂ (2×25 mL). The combined organiclayers were washed with brine (1×50 mL), dried over sodium sulfate,filtered and concentrated under vacuum to give a residue. The residuewas purified by silica gel chromatography (Ethyl acetate/Methanol=20/1to 3/1). The residue was further purified by prep-HPLC (column:Phenomenex Gemini 150*25 mm*10 um; mobile phase: [water (0.05% ammoniahydroxide v/v)-ACN]; B %: 48%-78%, 12 min). Title compound2-[(2S)-4-[7-(3-methoxy-2-methyl-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 324, 35.2 mg, 63.6 umol, 16% yield, 98.7% purity) was obtainedas a white solid. LCMS [ESI, M+1]: 546.

SFC condition: “OD-3S_3_40_3 ML Column: Chiralcel OD-3 100×4.6 mm I.D.,3 um, Mobile phase: 40% methanol (0.05% DEA) in CO₂ Flow rate: 3 mL/minWavelength: 220 nm”.

¹H NMR (400 MHz, chloroform-d) δ=7.17 (t, J=8.4 Hz, 1H), 6.73 (d, J=8.0,1H) 6.68 (d, J=8.4, 1H), 6.59 (br s, 1H), 6.46-6.34 (m, 1H), 5.83 (br d,J=10.0 Hz, 1H), 5.10 (br s, 1H), 4.39 (dd, J=5.2, 10.4 Hz, 1H),4.20-4.09 (m, 2H), 4.06 (s, 2H), 4.02-3.92 (m, 2H), 3.85 (s, 3H), 3.59(br s, 1H), 3.31 (br d, J=12.0 Hz, 1H), 3.22 (br d, J=11.6 Hz, 1H),3.17-3.02 (m, 3H), 3.02-2.62 (m, 6H), 2.49 (s, 3H), 2.36-2.25 (m, 1H),2.22 (s, 3H), 2.13-1.99 (m, 1H), 1.91-1.70 (m, 2H).

Example 325

2-(1-acryloyl-4-(7-(7-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: benzyl(2S)-2-(cyanomethyl)-4-[7-(2-cyanophenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1H-carboxylate.To a mixture of benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(Intermediate 65, 320 mg, 633 umol, 1 eq) and 2-bromobenzonitrile (230mg, 1.27 mmol, 2 eq) in toluene (30 mL) was added Cs₂CO₃ (619 mg, 1.90mmol, 3 eq), RuPhos (59.1 mg, 127 umol, 0.2 eq), Pd₂(dba)₃ (58.0 mg,63.3 umol, 0.1 eq) in one portion. The mixture was degassed and purgedwith N₂ for 3 times, then heated to 90° C. and stirred for 5 hours. Thereaction mixture was diluted with water (10 mL) and extracted with ethylacetate (30 mL×3). The combined organic layers were washed with water(30 mL×1), dried over sodium sulfate, filtered and concentrated underreduced pressure to give a residue. The residue was purified by reversedphase flash [water (0.1% FA)/acetonitrile]. The desired fractions werecollected and neutralized with saturated NaHCO₃ solution (5 mL) andextracted with ethyl acetate (100 mL). The separated organic layer wasdried over sodium sulfate, filtered and concentrated under vacuum.Compound benzyl(2S)-2-(cyanomethyl)-4-[7-(2-cyanophenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(139 mg, 210 umol, 33% yield, 91.5% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 607.

¹H NMR (400 MHz, chloroform-d) δ=7.62 (dd, J=1.2, 7.6 Hz, 1H), 7.56-7.49(m, 1H), 7.42-7.33 (m, 5H), 7.09-7.00 (m, 2H), 5.21 (s, 2H), 4.68 (br s,1H), 4.38 (br dd, J=4.8, 10.4 Hz, 1H), 4.26 (s, 2H), 4.19-4.01 (m, 3H),3.92 (br d, J=11.6 Hz, 1H), 3.78 (br d, J=12.0 Hz, 1H), 3.44-3.21 (m,3H), 3.15-2.95 (m, 3H), 2.85-2.61 (m, 4H), 2.49 (s, 3H), 2.34-2.23 (m,1H), 2.12-2.00 (m, 1H), 1.92-1.72 (m, 3H).

Step B:2-[4-[(3S)-3-(cyanomethyl)piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]benzonitrile.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[7-(2-cyanophenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(160 mg, 264 umol, 1 eq) in MeOH (12 mL) was added NH₃·MeOH (20 mL) andPd/C (20 mg, 10% purity) under N. The suspension was degassed undervacuum and purged with H₂ several times. The mixture was stirred underH₂ (15 psi) at 25° C. for 1 hour. The catalyst was filtered off and thefiltrate was concentrated under reduced pressure to give a residue. Thecrude product was used directly in the next step without purification.Compound2-[4-[(3S)-3-(cyanomethyl)piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]benzonitrile(119 mg, crude) was obtained as a green solid. LCMS [ESI, M+1]: 473.

Step C:2-[4-[(3S)-3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]benzonitrile.To a mixture of2-[4-[(3S)-3-(cyanomethyl)piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]benzonitrile(119 mg, crude) and prop-2-enoyl prop-2-enoate (31.8 mg, 252 umol) inDCM (5 mL) was added TEA (127 mg, 1.26 mmol, 175 uL) in portion at 0° C.under N₂. The mixture was heated to 25° C. and stirred for 0.5 hour. Thereaction mixture was quenched by addition saturated NaHCO₃ (5 mL) at 0°C., and then extracted with DCM (10 mL×3). The combined organic layerswere washed with water (15 mL×1), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by prep-HPLC (column: Phenomenex Gemini 150*25 mm*10 um; mobilephase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 43%-73%, 12 min).Title compound2-[4-[(3S)-3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]benzonitrile(EXAMPLE 325, 35.1 mg, 65.1 umol, two steps 25% yield, 97.5% purity) wasobtained as a colorless oil. LCMS [ESI, M+1]: 527.

¹H NMR (400 MHz, chloroform-d) δ 7.62 (d, J=8.0 Hz, 1H), 7.54 (t, J=8.4Hz, 1H), 7.10-7.00 (m, 2H), 6.59 (br s, 1H), 6.45-6.34 (m, 1H), 5.84 (brd, J=10.4 Hz, 1H), 5.09 (br s, 1H), 4.38 (dd, J=5.2, 10.4 Hz, 1H), 4.27(s, 2H), 4.21-4.08 (m, 2H), 3.99 (br d, J=12.0 Hz, 2H), 3.86-3.52 (m,2H), 3.39 (br s, 2H), 3.18-2.99 (m, 3H), 2.97-2.59 (m, 5H), 2.49 (s,3H), 2.37-2.21 (m, 1H), 2.17-1.98 (m, 1H), 1.94-1.79 (m, 2H).

Example 326

2-((S)-1-acryloyl-4-(7-(7-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: methyl-3,4-dihydronaphthalen-1-yl) trifluoromethanesulfonate. Toa solution of 7-methyltetralin-1-one (2.5 g, 15.6 mmol, 1.0 eq) in DCM(40 mL) was added DIEA (6.05 g, 46.8 mmol, 8.15 mL, 3.0 eq) and Tf₂O(6.60 g, 23.4 mmol, 3.86 mL, 1.5 eq) in portions at 0° C., the reactionmixture was stirred at 0-20° C. for 3 hours under N₂. After completion,the reaction was added ice water (40 mL) slowly; the organic layer wasseparated, and then dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=1:0) to give (7-methyl-3,4-dihydronaphthalen-1-yl)trifluoromethanesulfonate (4.0 g, 13.7 mmol, 88% yield) as yellow oil.

¹H NMR (400 MHz, chloroform-d) δ 7.18 (s, 1H), 7.12-7.06 (m, 2H), 6.02(t, J=4.8 Hz, 1H), 2.85 (t, J=8.2 Hz, 2H), 2.54-2.45 (m, 2H), 2.37 (s,3H).

Step B: (7-methyl-1-naphthyl trifluoromethanesulfonate. To a solution of(7-methyl-3,4-dihydronaphthalen-1-yl) trifluoromethanesulfonate (4.0 g,13.7 mmol, 1.0 eq) in dioxane (80.0 mL) was added DDQ (6.21 g, 27.4mmol, 2.0 eq), the reaction mixture was stirred at 105° C. for 12 hours.After completion, the reaction was concentrated. The residue waspurified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=1:0). The product (7-methyl-1-naphthyl)trifluoromethanesulfonate (3.4 g, 11.7 mmol, 86% yield) was obtained asyellow oil.

¹H NMR (400 MHz, chloroform-d) δ 7.89-7.81 (m, 3H), 7.49-7.40 (m, 3H),2.60 (s, 3H).

Step C:benzyl(2S)-2-(cyanomethyl)-4-[7-(7-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a mixture of benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(Intermediate 65, 1.20 g, 2.37 mmol, 1.0 eq) and (7-methyl-1-naphthyl)trifluoromethanesulfonate (1.03 g, 3.56 mmol, 1.50 eq) in toluene (20.0mL) was added Cs₂CO₃ (1.55 g, 4.75 mmol, 2.0 eq), and Xphos-Pd-G3 (301mg, 356 umol, 0.15 eq), the mixture was stirred at 70° C. for 12 hoursunder N₂. After completion, the reaction mixture was added water (20.0mL), then extracted with ethyl acetate (2×15.0 mL), the combined organiclayer was dried over Na₂SO₁, filtered and concentrated. The residue waspurified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=3/1 to ethyl acetate:Methanol=20:1). The productbenzyl(2S)-2-(cyanomethyl)-4-[7-(7-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(820 mg, 1.22 mmol, 51% yield, 95.9% purity) was obtained as brownsolid. LCMS [ESI, M+1]: 646.

Step D:2-[(2S)-4-[7-(7-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[7-(7-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(790 mg, 1.22 mmol, 1.0 eq) in MeOH (15.0 mL) was added NH₃·MeOH (1.22mmol, 15.0 mL, 1.0 eq) and Pd/C (500 mg, 10% purity), the suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred under H₂ (15 Psi) at 20° C. for 0.5 hour. After completion, thereaction mixture was filtered through a pad of Celite, and the filtercake was washed with DCM (2×20 mL), the filtrate was concentrated. Theproduct2-[(2S)-4-[7-(7-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(490 mg, 934 umol, 76% yield, 97.5% purity) was obtained as white solidwhich was used for the next step without further purification. LCMS[ESI, M+1]: 512.

Step E:2-[(2S)-4-[7-(7-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a mixture of2-[(2S)-4-[7-(7-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(490 mg, 958 umol, 1.0 eq) in DCM (8.0 mL) was added DIEA (495 mg, 3.83mmol, 667 uL, 4.0 eq) and prop-2-enoyl prop-2-enoate (121 mg, 958 umol,1.0 eq) at 0° C., the reaction mixture was stirred at 20° C. for 0.5hour. After completion, the reaction mixture was quenched with MeOH (5.0mL), and concentrated. The residue was purified by column chromatography(Base Al₂O₃, Ethyl acetate/Methanol=20/1), the obtained crude productwas concentrated and re-purified by prep-HPLC ((column: PhenomenexGemini 150*25 mm*10 um; mobile phase: [water (0.05% ammonia hydroxidev/v)-ACN]; B %: 57%-87%, 12 min), the obtained product was concentrated,and then under lyophilization. Title compound2-[(2S)-4-[7-(7-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 326, 133 mg, 235 umol, 25% yield, 99.6% purity) was obtained aswhite solid. LCMS [ESI, M+1]: 566.

¹H NMR (400 MHz, chloroform-d) δ 8.00 (s, 1H), 7.78 (d, J=8.4 Hz, 1H),7.59 (d, J=8.0 Hz, 1H), 7.43-7.32 (m, 2H), 7.13 (d, J=7.2 Hz, 1H),6.69-6.49 (m, 1H), 6.42 (dd, J=1.2, 16.8 Hz, 1H), 5.85 (br d, J=10.8 Hz,1H), 5.20-4.52 (m, 1H), 4.42 (dd, J=4.8, 10.4 Hz, 1H), 4.36-4.24 (m,2H), 4.22-4.10 (m, 2H), 4.06-3.95 (m, 2H), 3.76-3.22 (m, 4H), 3.21-3.07(m, 2H), 3.04-2.63 (m, 5H), 2.56 (s, 3H), 2.51 (s, 3H), 2.35-2.26 (m,1H), 2.14-2.02 (m, 1H), 1.92-1.75 (m, 3H).

Example 327

2-((S)-1-acryloyl-4-(2-(((2S,4R)-4-methoxy-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step 1: 1-tert-butyl 2-methyl(2S,4R)-4-methoxypyrrolidine-1,2-dicarboxylate. To a solution of1-tert-butyl 2-methyl(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (9g, 36.7 mmol, 1 eq) in CH₃CN (150 mL) was added Ag₂O (25.5 g, 110 mmol,3 eq) and CH₃I (54.3 g, 383 mmol, 23.8 mL, 10.4 eq). The mixture wasstirred at 25° C. for 12 hours. The reaction mixture was filtered andthe filter was concentrated. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=20/1 to 3:1).Compound 1-tert-butyl 2-methyl(2S,4R)-4-methoxypyrrolidine-1,2-dicarboxylate (9 g, 347 mmol, 95%yield) was obtained as a colorless oil.

¹H NMR (400 MHz, chloroform-d) δ=3.94-3.79 (m, 1H), 3.66 (dd, J=3.2,11.2 Hz, 1H), 3.44-3.34 (m, 2H), 3.28 (s, 3H), 2.92-2.53 (m, 2H),2.40-2.25 (m, 4H), 2.12-1.99 (m, 1H), 1.89-1.79 (m, 1H).

Step 2: [(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methanol. To asolution of 1-tert-butyl 2-methyl(2S,4R)-4-methoxypyrrolidine-1,2-dicarboxylate (5 g, 19.28 mmol, 1 eq)in THF (100 mL) was added LiAlH₄ (2.20 g, 57.8 mmol, 3 eq). The mixturewas stirred at 80° C. for 2 hours. The reaction mixture was quenchedwith saturated Na₂SO₄ aqueous solution (6 mL). Then the mixture wasfiltered and the filter was concentrated Compound[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methanol (1.8 g, 12.4 mmol,64% yield) was obtained as a colourless oil and used to next stepdirectly without purification.

¹H NMR (400 MHz, chloroform-d) δ 4.43-4.23 (m, 1H), 3.45-3.90 (m, 1H),3.78-3.69 (m, 3H), 3.68-3.43 (m, 2H), 3.32 (s, 3H), 2.43-2.24 (m, 1H),2.12-1.95 (m, 1H), 1.52-1.33 (m, 9H).

Step A: benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of [(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methanol(600 mg, 4.13 mmol, 3 ee) and benzyl(2S)-2-(cyanomethyl)-4-[2-methylsulfinyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(800 mg, 1.38 mmol, 1 eq) in THF (10 mL) was added t-BuONa (397 mg, 4.13mmol, 3 eq). The mixture was stirred at 25° C. for 0.5 hour. Thereaction mixture was diluted with ethyl acetate (30 mL) and washed withwater (20 mL). The organic layers was washed with brine (20 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (SiO₂, Ethylacetate/MeOH=200/1 to 20:1). Compound benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(910 mg, 1.28 mmol, 93% yield, 93% purity) was obtained as a yellow oil.LCMS [ESI, M+1]: 662.

Step B:2-[(2S)-4-[2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.NH₃ was bubbled in MeOH (80 mL) at −60° C. for 10 minutes. To a solutionof benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(850 mg, 1.28 mmol, 1 eq) in MeOH (30 mL) was added above NH₃·MeOH (20mL) and dry Pd/C (500 mg, 10% purity) under N₂. The suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred under H₂ (15 psi) at 25° C. for 1 hour. The reaction mixture wasfiltered and the filter was concentrated. Compound2-[(2S)-4-[2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(620 mg, 1.18 mmol, 91% yield) was obtained as a colourless oil and usedto next step directly without purification. LCMS [ESI, M+1]: 528.

Step C:2-[(2S)-4-[2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(620 mg, 1.18 mmol, 1 eq) in dichloromethane (10 mL) was added TEA (1.19g, 11.7 mmol, 1.64 mL, 10 eq) at 0° C. After addition, and prop-2-enoylprop-2-enoate (118 mg, 940 umol, 0.8 eq) in dichloromethane (1 mL) wasadded dropwise at 0° C. The resulting mixture was stirred at 25° C. for1 hour. The reaction mixture was quenched with saturated NaHCO₃ aqueoussolution (1 mL). Then diluted with water (20 mL) and extracted withdichloromethane (20 mL×3). The combined organic layers were washed withbrine (20 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by columnchromatography (Al₂O₃ EA/MeOH-100/1 to 10:1) and further purified byprep-HPLC (column: Phenomenex Gemini 150*25 mm*10 um; mobile phase:[water (0.05% ammonia hydroxide v/v)-ACN]; B %: 45%-75%, 12 min). Tidecompound2-[(2S)-4-[2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(101 mg, 167 umol, 14% yield, 96.6% purity) was obtained as a whitesolid by lyophilisation. LCMS [ESI, M+1]: 582.

SFC condition: Column: Chiralcel OJ-3 100×4.6 mm I.D., 3 um, Mobilephase: methanol (0.05% DEA) in CO₂ from 5% to 40%, Flow rate: 3 mL/min,Wavelength: 220 nm.

¹H NMR (400 MHz, chloroform-d) δ=8.26-8.17 (m, 1H), 7.91-7.82 (m, 1H),7.61 (d, J=8.0 Hz, 1H), 7.55-7.47 (m, 2H), 7.44 (t, J=8.0 Hz, 1H), 7.15(d, J=7.6 Hz, 1H), 6.60 (br s, 1H), 6.41 (d, J=16.8 Hz, 1H), 5.84 (br d,J=10.8 Hz, 1H), 5.21-4.53 (m, 1H), 4.42 (dd, J=4.4, 10.4 Hz, 1H),4.34-4.17 (m, 3H), 4.13 (br d, J=13.6 Hz, 1H), 4.04-3.93 (m, 2H),3.70-3.42 (m, 3H), 3.31 (s, 5H), 3.22-2.69 (m, 7H), 2.48 (s, 3H), 2.33(dd, J=5.6, 9.6 Hz, 1H), 2.14-2.04 (m, 1H), 2.02-1.91 (m, 1H).

Example 328

2-((S)-1-acryloyl-4-(7-(3-fluoro-2-(trifluoromethyl)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: benzyl(2S)-2-(cyanomethyl)-4-[7-[3-fluoro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a mixture of benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1.0 g, 1.98 mmol, 1.0 eq) and1-bromo-3-fluoro-2-(trifluoromethyl)benzene (2.88 g, 11.9 mmol, 6.0 eq)in toluene (20.0 mL) was added Cs₂CO₃ (1.29 g 3.96 mmol, 2.0 eq), RuPhos(185 mg, 396 umol, 0.2 eq) and Pd₂(dba)₃ (272 mg, 297 umol, 0115 eq),the mixture was stirred at 100° C. for 18 hours under N₂. Aftercompletion, the reaction mixture was added water (30.0 mL), thenextracted with ethyl acetate (2×20.0 mL), the combined organic layer wasdried over Na₂SO₄, filtered and concentrated. The residue was purifiedby column chromatography (SiO₂, Petroleum ether/Ethyl acetate=3/1 toEthyl acetate:Methanol=20:1). The obtained product was then purified byreversed phase flash again (C18, 0.1% FA in MeCN), the obtained productwas adjusted with NaHCO₃ solid to pH˜7, the mixture was extracted withethyl acetate (2×15.0 mL), and the organic layer was dried over Na₂SO₄,filtered and concentrated. The product benzyl(2S)-2-(cyanomethyl)-4-[7-[3-fluoro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(160 mg, 236 umol, 12% yield, 98% purity) was obtained as brown oil.LCMS [ESI, M+1]: 668.

Step B:2-[(2S)-4-[7-[3-fluoro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[7-[3-fluoro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(460 mg, 689 umol, 1.0 eq) in MeOH (10 mL) was added Pd/C (300 mg, 10%purity) and NH₃·MeOH (10 mL), the suspension was degassed under vacuumand purged with H₂ several times. The mixture was stirred under H₂ (15Psi) at 20° C. for 10 mins. After completion, the reaction was filteredthrough a pad of Celite, and the filtrate was concentrated to give2-[(2S)-4-[7-[3-fluoro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(320 mg, 591 umol, 86% yield, 98% purity) as yellow solid. LCMS [ESI,M+1]: 534.

Step C:2-[(2S)-4-[7-[3-fluoro-2-(trifluoromethyl]phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a mixture of2-[(2S)-4-[7-[3-fluoro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(320 mg, 599 umol, 1.0 eq) in DCM (8.0 mL) was added DIEA (310 mg, 2.40mmol, 418 uL, 4.0 eq) and prop-2-enoyl prop-2-enoate (75.6 mg, 599 umol,1.0 eq) at 0° C., the reaction mixture was stirred at 20° C. for 0.5hour. After completion, the reaction mixture was quenched with MeOH (5.0mL), and concentrated. The residue was purified by column chromatography(Base Al₂O₃, Ethyl acetate/Methanol=20/1), then the obtained product wasconcentrated and purified again by prep-HPLC (column: Gemini 150*25 5 u;mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 51%-81%,12 min). Title compound2-[(2S)-4-[7-[3-fluoro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(86.8 mg, 145 umol, 24% yield, 98% purity) was obtained as white solidLCMS [ESI, M+1]: 588.

¹H NMR (400 MHz, chloroform-d) δ 7.55-7.45 (m, 1H), 7.08 (d, J=8.4 Hz,1H), 7.02-6.91 (m, 1H), 6.68-6.53 (m, 1H), 6.41 (dd, J=1.6, 16.8 Hz,1H), 5.85 (br d, J=10.8 Hz, 1H), 5.11-4.52 (m, 1H), 4.39 (dd, J=4.8,10.4 Hz, 1H), 4.17 (dd, J=6.8, 10.4 Hz, 1H), 4.14-4.07 (m, 3H), 3.98 (brd, J=11.6 Hz, 1H), 3.72-3.52 (m, 1H), 3.42-3.25 (m, 2H), 3.23-2.58 (m,9H), 2.49 (s, 3H), 2.35-2.25 (m, 1H), 2.13-2.01 (m, 1H), 1.91-1.73 (m,3H).

Example 329

2-[(2S)-4-[2-[[(2R)-1-(2-hydroxyethyl)pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Insert:[(2R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-yl]methanol.A mixture of [(2R)-pyrrolidin-2-yl]methanol (0.50 g, 4.94 mmol, 481 uL,1.00 eq), 2-bromoethoxy-tert-butyl-dimethyl-silane (1.18 g, 4.94 mmol,1.00 eq) and K₂CO₃ (3.42 g, 24.7 mmol, 5.00 eq) in acetonitrile (30.0mL) was stirred at 83° C. for 12 hours. The mixture was filtered and thefiltrate was concentrated under vacuum. The residue was purified bycolumn chromatography (SiO₂, ethyl acetate/methanol=10/1) to give[(2R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-yl]methanol(0.50 g, 1.93 mmol, 39% yield) as a colorless oil.

¹H NMR (400 MHz, chloroform-d) δ=3.70 (t, J=6.0 Hz, 2H), 3.60 (dd,J=3.6, 10.8 Hz, 1H), 3.36 (dd, J=3.6, 10.8 Hz, 1H), 3.20 (td, J=4.4, 9.2Hz, 1H), 2.89 (td, J=6.4, 12.8 Hz, 1H), 2.74-2.65 (m, 1H), 2.50 (td,J=5.2, 12.8 Hz, 1H), 2.42-2.32 (m, 1H), 1.92-1.81 (m, 1H), 1.78-1.66 (m,3H), 0.90 (d, J=0.8 Hz, 9H), 0.07 (d, J=0.4 Hz, 6H).

Step A: benzyl(2S)-4-[2-4[(2R)-1-[2-(tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.To a solution of[(2R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-yl]methanol(344 mg, 1.33 mmol, 1.10 eq) in THF (10.0 mL) was added t-BuONa (232 mg,2.41 mmol, 2.00 eq) and benzyl(2S)-2-(cyanomethyl)-4-[2-methylsulfinyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(Intermediate 64, 0.70 g, 1.21 mmol, 1.00 eq) at 0° C. After stirred at0° C. for 0.5 h, the mixture was diluted with ethyl acetate (10.0 mL),washed with water (1×10.0 mL), dried over Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by columnchromatography (Al₂O₃, ethyl acetate/petroleum ethyl=3/1) to give benzyl(2S)-4-[2-[[(2R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(0.60 g, 704 umol, 58% yield) as a yellow solid. LCMS [ESI, M+1]: 776.

¹H NMR (400 MHz, chloroform-d) δ=8.23-8.18 (m, 1H), 7.90-7.83 (m, 1H),7.61 (d, J=8.4 Hz, 1H), 7.54-7.47 (m, 2H), 7.46-7.34 (m, 6H), 7.14 (d,J=7.2 Hz, 1H), 5.21 (s, 2H), 4.70 (br s, 1H), 4.34 (br dd, J=4.2, 10.6Hz, 1H), 4.30-4.20 (m, 2H), 4.17-3.89 (m, 4H), 3.75 (t, J=6.8 Hz, 2H),3.49 (br d, J=8.4 Hz, 1H), 3.38-3.13 (m, 4H), 3.10-2.90 (m, 4H),2.89-2.70 (m, 3H), 2.63-2.52 (m, 1H), 2.41-2.31 (m, 1H), 2.04-1.94 (m,1H), 1.87-1.73 (m, 3H), 0.88 (s, 9H), 0.05 (d, J=1.2 Hz, 6H).

Step B:2-[(2S)-4-[2-[[(2R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.NH₃ was bubbled in methanol (50.0 mL) at −78° C. for 10 minutes. Benzyl(2S)-4-[2-[[(2R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(0.60 g, 773 umol, 1.00 eq) and Pd/C (0.1 g, 10% purity) were added intothe above solution. After stirred at 25° C. for 1 hour under H₂ at 15psi, the catalyst was filtered off and the filter cake was wash with THF(10.0 mL). The filtrate was concentrated under vacuum to give2-[(2S)-4-[2-[[(2R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(0.50 g, crude) as a yellow oil and used into next step without furtherpurification. LCMS [ESI, M/2+1]: 321.

Step C:2-[(2S)-4-[2-[[(2R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[2-[[(2R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(0.50 g, crude) and TEA (394 mg, 3.89 mmol, 542 uL) in dichloromethane(5.00 mL) was added prop-2-enoyl prop-2-enoate (98.2 mg, 779 umol) at−40° C. After stirred at 25° C. for 1 hour, the mixture was quenchedwith saturated sodium bicarbonate (0.10 mL) and concentrated undervacuum. The residue was purified by column chromatography (Al₂O₃,methanol/ethyl acetate=10/1) to give2-[(2S)-4-[2-[[(2R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(0.35 g, 427 umol, two steps 55% yield) as a yellow solid. LCMS [ESI,M+1]: 696.

Step D:2-[(2S)-4-[2-[[(2R)-1-(2-hydroxyethyl)pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.A mixture of2-[(2S)-4-[2-[[(2R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(0.35 g, 503 umol, 1.00 eq), KF (146 mg, 2.51 mmol, 58.9 uL, 5.00 eq)and 18-CROWN-6 (665 mg, 2.51 mmol, 5.00 eq) in THF (5.00 mL) was stirredat 40° C. for 12 hours. The mixture was concentrated under vacuum. Theresidue was purified by reverse phase flash [water (TFA,0.10%)/acetonitrile] and prep-HPLC (column: Phenomenex Gemini 150*25mm*10 um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %:45%-75%, 12 min). The desired fractions were collected and lyophilizedto give title compound2-[(2S)-4-[2-[[(2R)-1-(2-hydroxyethyl)pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 329, 146 mg, 245 umol, 49% yield, 97.7% purity) as a whitesolid. LCMS [ESI, M+1]: 582.

SFC condition: “Column: Chiralcel OJ-3 100×4.6 mm I.D., 3 um, Mobilephase: methanol (0.05% DEA) in CO₂ from 5% to 40%, Flow rate: 3 mL/min,Wavelength: 220 nm”.

¹H NMR (400 MHz, chloroform-d) δ=8.29-8.18 (m, 1H), 7.95-7.82 (m, 1H),7.61 (d, J=8.0 Hz, 1H), 7.56-7.47 (m, 2H), 7.44 (t, J=7.6 Hz, 1H), 7.15(d, J=7.2 Hz, 1H), 6.60 (br s, 1H), 6.46-6.31 (m, 1H), 5.83 (br d,J=10.8 Hz, 1H), 5.19-4.47 (m, 1H), 4.38-4.22 (m, 3H), 4.21-4.09 (m, 2H),4.02 (br d, J=11.2 Hz, 2H), 3.71-3.57 (m, 2H), 3.53-3.27 (m, 3H),3.22-2.76 (m, 9H), 2.62 (td, J=3.6, 12.4 Hz, 1H), 2.41-2.28 (m, 1H),2.11-1.95 (m, 1H), 1.89-1.77 (m, 3H).

Example 330

2-[(2-S)-4-[7-[3-methoxy-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Insert: 1-bromo-3-methoxy-2-(trifluoromethyl)benzene. To a solution ofMeOH (264 mg, 8.23 mmol, 333 uL, 2.00 eq) in DMF (25.0 mL) was added NaH(329 mg, 8.23 mmol, 60% purity in mineral oil, 2.00 eq). The solutionwas mixed at room temperature (25° C.) for 30 minutes after which time1-bromo-3-fluoro-2-(trifluoromethyl)benzene (1.00 g, 4.12 mmol, 1.00 eq)was added. The solution was then stirred at 25° C. for 0.5 hour. Uponcompletion, the mixture was diluted with water (50 mL) and extractedwith EtOAc (2×50 mL). The organic layers were washed with brine (30 mL),dried over Na₂SO₄ and concentrated under vacuum. The residue waspurified by silica gel chromatography (PE/EtOAc 1/0 to 100/1) to give1-bromo-3-methoxy-2-(trifluoromethyl)benzene (880 mg, 3.11 mmol, 75%yield, 90.0% purity) as a colorless oil.

¹H NMR (400 MHz, chloroform-d) δ=7.34-7.27 (m, 2H), 6.99 (br d, J=7.2Hz, 1H), 3.91 (s, 3H).

Step A:(2S)-2-(cyanomethyl)-4-[7-[3-methoxy-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(Intermediate 65, 550 mg, 1.09 mmol, 1.00 eq),1-bromo-3-methoxy-2-(trifluoromethyl)benzene (416 mg, 1.63 mmol, 1.50eq), RuPhos (152 mg, 326 umol, 0.30 eq), Cs₂CO₃ (1.06 g, 3.26 mmol, 3.00eq) and Pd₂(dba)₃ (149 mg, 163 umol, 0.15 eq) in toluene (30.0 mL) wasde-gassed and then heated to 90° C. for 12 hours under N₂. Uponcompletion, the mixture was concentrated under vacuum. The residue wasdiluted with water (10 mL) and extracted with EtOAc (2×40 mL). Theorganic layers were dried over Na₂SO₄ and concentrated under vacuum. Theresidue was purified by reversed-phase flash [water (0.1%FA)/acetonitrile]. The collected desired fractions were neutralized withsaturated sodium bicarbonate solution, concentrated under vacuum toremove MeCN and extracted with EtOAc (2×100 mL). The organic layers weredried over Na₂SO₄ and concentrated under vacuum to give benzyl(2S)-2-(cyanomethyl)-4-[7-[3-methoxy-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(230 mg, 321 umol, 30% yield, 94.9% purity) as a yellow solid. LCMS[ESI, M+1]: 680.

Step B: 2-[(2S)-4-[7-[3-methoxy-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[7-[3-methoxy-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(230 mg, 338 umol, 1.00 eq) in MeOH (4.00 mL) was added NH₃/MeOH (7 M,4.00 mL), Pd/C (70.0 mg, 10% purity) under N₂. The suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred under H₂ (15 psi) at 25° C. for 1 hour. Upon completion, thecatalyst was filtered off and the filtrate was concentrated to give2-[(2S)-4-[7-[3-methoxy-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(150 mg, 242 umol, 72% yield, 88.1% purity) as a yellow solid which wasused directly in the next step without further purification. LCMS [ESI,M+1]: 546.

Step C:2-[(2S)-4-[7-[3-methoxy-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of 2-[(2S)-4-[7-[3-methoxy-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(150 mg, 242 umol, 1.00 eq) and TEA (122 mg, 1.21 mmol, 168 uL, 5.00 eq)in DCM (3.00 mL) was added prop-2-enoyl prop-2-enoate (30.5 mg, 242umol, 1.00 eq) dropwise at 0° C. The mixture was stirred at 25° C. for 1hour. Upon completion, the mixture was quenched with MeOH (0.1 mL) andwater (2 mL). Layers were separated. The aqueous phase was extractedwith EtOAc (2×8 mL). The combined organic layers were dried over Na₂SO₄and concentrated under vacuum. The residue was purified by prep-TLC(EtOAc/MeOH 7/1) and then prep-HPLC (column: Gemini 150*25 5 u; mobilephase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 50%-80%, 12 min)and lyophilized to give2-[(2S)-4-[7-[3-methoxy-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 330, 28.2 mg, 45.6 umol, 19% yield, 96.8% purity) as a whitesolid. LCMS [ESI, M+1]: 600.

SFC condition: Column: Chiralcel OD-3 100×4.6 mm I.D., 3 um Mobilephase: methanol (0.05% DEA) in CO₂ from 5% to 40% Flow rate: 3 mL/minWavelength: 220 nm.

¹H NMR (400 MHz, chloroform-d) δ=7.42 (t, J=8.4 Hz, 1H), 6.84 (d, J=8.0Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 6.59 (br s, 1H), 6.46-6.34 (m, 1H),5.83 (br d, J=10.4 Hz, 1H), 5.09 (br s, 1H), 4.37 (dd, J=5.2, 10.8 Hz,1H), 4.21-4.02 (m, 4H), 4.01-3.77 (m, 5H), 3.75-3.21 (m, 3H), 3.20-2.98(m, 3H), 2.97-2.56 (m, 5H), 2.48 (s, 3H), 2.35-2.23 (m, 1H), 2.12-1.98(m, 1H), 1.91-1.72 (m, 3H).

Example 331

2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A:2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(700 mg, 1.16 mmol, 1.00 eq, 2 HC) and TEA (1.76 g, 17.4 mmol, 2.42 mL,15.0 eq) in anhydrous DCM (17.0 mL) was added prop-2-enoyl prop-2-enoate(146 mg, 1.16 mmol, 1.00 eq) at 0° C. The mixture was stirred for 1 hourat 25° C. Upon completion, the mixture was quenched with MeOH (1 mL) andwater (10 mL). The separated aqueous phase was extracted with EtOAc(2×20 mL). The combined organic layers were dried over Na₂SO₄ andconcentrated under vacuum. The residue was purified by silica gelchromatography (petroleum ether/ethyl acetate 2/1 to 0/1) and thenprep-HPLC (column: Phenomenex Gemini 150*25 mm*10 um; mobile phase:[water (0.05% ammonia hydroxide v/v)-ACN]; B %: 52%-82%, 12 min). Thedesired fractions were collected and lyophilized to give title compound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 331, 122 mg, 205 umol, 18% yield, 98.5% purity) as a whitesolid. LCMS [ESI, M+1]: 586.

SFC condition: Column: Chiralpak AD-3 100×4.6 mm I.D., 3 um, Mobilephase: 40% iso-propanol (0.05% DEA) in CO₂ Flow rate: 3 mL/minWavelength: 220 nm.

¹H NMR (400 MHz, chloroform-d) δ=7.76 (br d, J=8.4 Hz, 1H), 7.62 (t,J=7.6 Hz, 1H), 7.53 (d, J=7.2 Hz, 1H), 7.45 (td, J=7.6, 13.2 Hz, 1H),7.37-7.31 (m, 1H), 7.27-7.17 (m, 1H), 6.59 (br s, 1H), 6.45-6.33 (m,1H), 5.83 (br d, J=10.4 Hz, 1H), 5.08 (br s, 1H), 4.49-4.30 (m, 2H),4.22-3.66 (m, 5H), 3.63-3.32 (m, 2H), 3.32-2.97 (m, 5H), 2.91-2.52 (m,4H), 2.48 (d, J=2.4 Hz, 3H), 2.36-2.21 (m, 1H), 2.12-1.96 (m, t H),1.86-1.70 (m, 3H).

Example 332

2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: tert-butyl(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.To a solution of tert-butyl(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(450 mg, 751 umol, 1.0 eq) and[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methanol (218 mg, 1.50 mmol,2.0 eq) in toluene (20.0 mL) was added t-BuONa (144 mg, 1.50 mmol, 2.0eq). The mixture was stirred at 0° C. for 10 min. The reaction mixturewas quenched by addition H₂O (10.0 mL) at 20° C., and the reactionmixture was extracted with EA (20.0 mL×3). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated under reduced pressureto give a residue. The residue was purified by column chromatography(SiO₂, Petroleum ether/Ethyl acetate=1/1 to EA/MeOH=10/1). The producttert-butyl(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(0.30 g, 413 umol, 55% yield, 93.7% purity) was obtained as a whitesolid. LCMS [ESI, M+1]: 680.

Step B:2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(270 mg, 397 umol, 1.0 eq) in DCM (20 mL) was added TFA (3.08 g, 27.0mmol, 2.0 mL, 681 eq). The mixture was stirred at 20° C. for 10 min. Thereaction mixture was concentrated under reduced pressure to give aresidue. The product2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(300 mg, crude, 2TFA) was obtained as a yellow solid. LCMS [ESI, M+1]:580.

Step C:2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(300 mg, 371 umol, 1.0 eq, 2TFA) in DCM (3.0 mL) was added DIEA (480 mg,3.71 mmol, 647 μL, 10.0 eq). The mixture was stirred at 0° C. for 1hour. The reaction mixture was quenched by addition MeOH (10.0 mL) at20° C., and concentrated under reduced pressure to give a residue. Theresidue was purified by prep-HPLC (column: Phenomenex Gemini 150*25mm*10 um: mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %:50%-80%, 12 min). The residue was concentrated under reduced pressure toremove ACN, and then lyophilization. Tide compound2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(27.6 mg, 43.5 umol, two steps 10% yield, 100% purity) was obtained as awhite solid. LCMS [ESI, M+1]: 634.

¹H NMR (400 MHz, Chloroform-d) δ=7 44-7.37 (m, 1H), 7.32-7.40 (m, 1H)7.19 (d, J=8.4 Hz, 1H), 6.57 (br, d, J=14.1 Hz, 1H), 6.44-6.37 (m, 1H),5.84 (br, d, J=10.8 Hz, 1H), 5.1 (br, s, 1H), 4.45-4.35 (m, 1H), 4.19(br, dd, J=5.9, 10.9 Hz, 1H), 4.10 (s, 3H), 4.00-3.90 (m, 2H), 3.75-3.4(m, 2H), 3.40-3.00 (m, 8H), 3.00-2.65 (m, 5H), 2.45 (s, 3H), 2.38-2.28(m, 1H), 2.15-2.00 (m, 1H), 2.00-1.90 (m, 1H).

Example 333

2-[(2S)-4-[7-(7-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Insert: (7-fluoro-1-naphthyl) trifluoromethanesulfonate. To a solutionof 7-fluoronaphthalen-1-ol (980 mg, 6.04 mmol, 1 eq) and DIEA (2.34 g,18.1 mmol, 3.16 mL, 3 eq) in DCM (40 mL) was added Tf₂O (2.56 g, 9.07mmol, 1.50 mL, 1.5 eq) dropwise at −5° C. The mixture was stirred at 25°C. for 3 hours. Then the mixture was concentrated under vacuum. Theresidue was purified by silica gel chromatography (Petroleum ether/Ethylacetate=100/1 to 10/1). Compound (7-fluoro-1-naphthyl)trifluoromethanesulfonate (1.63 g, 5.54 mmol, 92% yield) was obtained asa colorless oil.

¹H NMR (400 MHz, chloroform-d) δ=7.92 (dd, J=5.6, 9.0 Hz, 1H), 7.87 (d,J=8.0 Hz, 1H), 7.70 (dd, J=2.4, 9.9 Hz, 1H), 7.56-7.50 (m, 1H),7.49-7.43 (m, 1H), 7.42-7.34 (m, 1H).

Step A: benzyl(2S)-2-(cyanomethyl)-4-[7-(7-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a mixture of benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(Intermediate 65, 330 mg, 463 umol, 1 eq), (7-fluoro-1-naphthyl)trifluoromethanesulfonate (273 mg, 927 umol, 2 eq), Pd₂(dba)₃ (84.9 mg,92.7 umol, 0.2 eq), RuPhos (64.9 mg, 139 umol, 0.3 eq) and Cs₂CO₃ (453mg, 1.39 mmol, 3 eq) in toluene (30 mL) was degassed and purged with N₂for 3 times, and then the mixture was stirred at 90° C. for 6 hoursunder N₂ atmosphere. The reaction mixture was added H₂O (1×200 mL) andethyl acetate (1×250 mL). The organic phase was separated, washed withbrine (1×200 mL), dried over sodium sulfate, filtered and concentratedunder reduced pressure to give a residue. The residue was purified byreversed phase flash [water (0.1% FA)/acetonitrile]. The desiredfractions were collected and neutralized to pH=7 with saturated NaHCO₃solution, and then extracted with ethyl acetate (1×200 mL). Theseparated organic layer was dried over sodium sulfate, filtered andconcentrated under vacuum. Compound benzyl(2S)-2-(cyanomethyl)-4-[7-(7-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 308 umol, 100% purity, 67% yield) was obtained as a yellow oil.LCMS [ESI, M+1]: 650.

¹H NMR (400 MHz, chloroform-d) δ=7.80-7.70 (m, 2H), 7.53 (d, J=8.4 Hz,1H), 7.36-7.24 (m, 6H), 7.24-7.16 (m, 1H), 7.10 (d, J=7.2 Hz, 1H),5.19-5.09 (m, 2H), 4.62 (br s, 1H), 4.51 (dd, J=6.0, 11.2 Hz, 1H), 4.26(dd, J=5.6, 11.3 Hz, 1H), 4.15 (s, 2H), 4.11-3.99 (m, 2H), 3.90 (br d,J=12.8 Hz, 1H), 3.38-3.11 (m, 5H), 3.08-2.95 (m, 2H), 2.93-2.71 (m, 3H),2.70-2.62 (m, 1H), 2.60 (s, 3H), 2.53-2.42 (m, 1H), 2.15-2.02 (m, 1H),1.96-1.75 (m, 3H).

Step B:2-[(2S)-4-[7-(7-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.A mixture of benzyl(2S)-2-(cyanomethyl)-4-[7-(7-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(810 mg, 1.25 mmol, 1 eq), Pd/C (400 mg, 10% purity) and NH₃ in MeOH (7M, 150 mL) was degassed and purged with H₂ for 3 times, and then themixture was stirred at 25° C. for 0.5 hr under H₂ atmosphere at 15 psipressure. The mixture was filtered and concentrated under vacuum.2-[(2S)-4-[7-(7-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(600 mg, 1.16 mmol, 93% yield, 99.4% purity) was obtained as a yellowoil. LCMS [ESI, M+1]: 516.

¹H NMR (400 MHz, chloroform-d) δ=7.89-7.79 (m, 2H), 7.61 (br d, J=8.4Hz, 1H), 7.40 (t, J=7.8 Hz, 1H), 7.32-7.24 (m, 1H), 7.19 (br d, J=7.6Hz, 1H), 4.51 (dd, J=5.6, 10.9 Hz, 1H), 4.30-4.19 (m, 3H), 4.05 (br d,J=12.4 Hz, 1H), 3.88 (br d, J=12.0 Hz, 1H), 3.37-3.21 (m, 4H), 3.19-3.09(m, 2H), 3.06-2.84 (m, 5H), 2.61-2.53 (m, 5H), 2.47-2.36 (m, 1H),2.19-2.08 (m, 1H), 1.97-1.76 (m, 3H).

Step C:2-[(2S)-4-[7-(7-fluoro-1-naphthyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a mixture of2-[(2S)-4-[7-(7-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(600 mg, 1.16 mmol, 1 eq) and TEA (589 mg, 5.82 mmol, 810 uL, 5 eq) inDCM (30 mL) was added prop-2-enoyl prop-2-enoate (117 mg, 931 umol, 0.8eq) at 0° C. The mixture was stirred at 25° C. for 1 hour. The reactionmixture was quenched with saturated NaHCO₃ solution (10 mL) at 0° C.,and then extracted with CH₂Cl₂ (2×30 mL). The combined organic layerswere washed with brine (1×50 mL), dried over sodium sulfate, filteredand concentrated under vacuum to give a residue. The residue waspurified by column chromatography (Al₂O₃, Ethyl acetate/Methanol=20/1 to3/1). The residue was purified by prep-HPLC (column: waters xbridge150*25 5 u; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 50%-80%, 10 min). Title compound2-[(2S)-4-[7-(7-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 333, 139 mg, 244 umol, 21% yield, 100% purity) was obtained asa white solid. LCMS [ESI, M+1]: 570.

SFC condition: “Column: Chiralpak AD-3 100×4.6 mm I.D., 3 um, Mobilephase: methanol (0.05% DEA) in CO₂ from 5% to 40%, Flow rate: 3 mL/min,Wavelength: 220 nm”.

¹H NMR (400 MHz, chloroform-d) δ=7.92-7.80 (m, 2H), 7.63 (d, J=8.0 Hz,1H), 7.42 (t, J=7.6 Hz, 1H), 7.33-7.25 (m, 1H), 7.20 (d, J=7.2 Hz, 1H),6.62 (br s, 1H), 6.47-6.37 (m, 1H), 5.85 (br d, J=10.8 Hz, 1H),5.27-4.52 (m, 1H), 4.41 (dd, J=4.8, 10.4 Hz, 1H), 4.25 (br s, 2H),4.22-4.10 (m, 2H), 4.09-3.87 (m, 2H), 3.77-3.25 (m, 2H), 3.24-3.06 (m,3H), 3.05-2.59 (m, 6H), 2.50 (s, 3H), 2.38-2.23 (m, 1H), 2.15-2.00 (m,1H), 1.99-1.81 (m, 3H).

Example 334

2-(1-acryloyl-4-(7-(7-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: tert-butyl (2R)-2-(benzyloxymethyl)pyrrolidine-1-carboxylate. Toa solution of NaH (1.11 g, 27.8 mmol, 60% purity, 1.2 eq) in THF (80 mL)was added a solution of tert-butyl(2R)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (4.67 g, 23.2 mmol, 1eq) in THF (20 mL) at 0° C. and the mixture was stirred at 0° C. for 1hour. BnBr (5.95 g, 34.8 mmol, 4.13 mL, 1.5 eq) was added dropwise at 0°C. and the mixture was stirred at 25° C. for 4 hours. The reactionmixture was quenched with saturated ammonium chloride solution (20 mL)at 0° C. and then diluted with ethyl acetate (2×100 mL). The organiclayers were washed with water (1×150 mL) and brine (1×150 mL), driedover sodium sulfate, filtered and concentrated under reduced pressure togive a residue. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=100/1 to 2/1). Compound tert-butyl(2R)-2-(benzyloxymethyl)pyrrolidine-1-carboxylate (5.03 g, 17.3 mmol,74% yield) was obtained as a colorless oil.

¹H NMR (400 MHz, chloroform-d) δ=7.37-7.14 (m, 5H), 4.47 (br s, 2H),4.07-3.77 (m, 1H), 3.67-3.07 (m, 4H), 2.08-1.68 (m, 4H), 1.38 (s, 9H).

Step B: (2R)-2-(benzyloxymethyl)pyrrolidine. To a mixture of tert-butyl(2R)-2-(benzyloxymethyl)pyrrolidine-1-carboxylate (4 g, 13.7 mmol, 1 eq)in dioxane (80 mL) was added HCl/dioxane (4 M, 120 mL, 35 eq). Themixture was stirred at 25° C. for 2 hours. The reaction mixture wasconcentrated under reduced pressure to give a residue. The crude productwas used directly into next step without further purification. Compound(2R)-2-(benzyloxymethyl)pyrrolidine (3.13 g, crude, HCl) was obtained asa white solid.

¹H NMR (400 MHz, DMSO-d₆) δ=9.76 (br s, 1H), 9.11 (br s, 1H), 7.43-7.23(m, 5H), 4.55 (s, 2H), 3.75-3.61 (m, 3H), 3.13 (br d, J=4.4 Hz, 2H),2.07-1.76 (m, 3H), 1.66-1.56 (m, 1H).

Step C: (2R)-2-(benzyloxymethyl)-1-ethyl-pyrrolidine. To a mixture of(2R)-2-(benzyloxymethyl)pyrrolidine (3 g, crude, HCl) and iodoethane(2.05 g, 13.2 mmol, 1.05 mL) in CH₃CN (65 mL) was added K₂CO₃ (1.82 g,13.2 mmol) in portion at 25° C. The mixture was stirred at 25° C. for 1h, then heated to 78° C. and stirred for 11 hours. The reaction mixturewas diluted with water (20 mL) and extracted with ethyl acetate (50mL×3). The combined organic layers were washed with water (30 mL×2),dried over sodium sulfate, filtered and concentrated under reducedpressure to give a residue. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to Ethylacetate/Methanol=5/1). Compound(2R)-2-(benzyloxymethyl)-1-ethyl-pyrrolidine (2.41 g, 10.4 mmol, twosteps 79° yield, 95% purity) was obtained as a brown oil.

¹H NMR (400 MHz, chloroform-d) δ=7.30-7.18 (m, 5H), 4.47 (s, 2H), 3.46(dd, J=4.8, 9.2 Hz, 1H), 3.30 (dd, J=6.4, 9.2 Hz, 1H), 3.10 (ddd, J=2.4,6.8, 8.8 Hz, 1H), 2.88 (qd, J=7.6, 12.4 Hz, 1H), 2.62-2.49 (m, 1H), 2.24(qd, J=7.2, 12.4 Hz, 1H), 2.14-2.03 (m, 1H), 1.92-1.80 (m, 1H),0.78-1.51 (m, 3H), 1.04 (t, J=7.2 Hz, 3H).

Step D: [(2R)-1-ethylpyrrolidin-2-yl]methanol. To a solution of(2R)-2-(benzyloxymethyl)-1-ethyl-pyrrolidine (2 g, 9.12 mmol, 1 eq) inMeOH (60 mL) was added HCl/MeOH (4 M, 30 mL, 13.2 eq) to adjusting thepH to 3-4, and then Pd(OH)₂/C (300 mg, 20% purity) was added under N₂.The suspension was degassed under vacuum and purged with H₂ three times.The mixture was stirred under H₂ (50 psi) at 25° C. for 12 hours. Thecatalyst was filtered and concentrated under reduced pressure to give aresidue. The crude product was used directly into the next step withoutfurther purification. Compound [(2R)-1-ethylpyrrolidin-2-yl]methanol(1.68 g, crude, HCl) was obtained as a yellow solid.

¹H NMR (400 MHz, methanol-d₄) δ=3.88 (dd, J=3.6, 12.4 Hz, 1H), 3.75-3.45(m, 4H), 3.21-3.08 (m, 2H), 2.30-1.82 (m, 4H), 1.37 (t, J=7.2 Hz, 3H).

Step E: benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2R)-1-ethylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.[(2R)-1-ethylpyrrolidin-2-yl]methanol (334 mg, 2.01 mmol, 1.95 eq, HCl)was dissolved into saturated sodium carbonate solution (5 mL) and thenextracted ethyl acetate (2×10 mL). The extracts were dried over sodiumsulfate, filtered and concentrated under vacuum. To a mixture of benzyl(2S)-2-(cyanomethyl)-4-[2-methylsulfinyl-7-(1-naphthyl)-6,8-dihydro-5N-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(Intermediate 64, 600 mg, 1.03 mmol, 1 eq) and the above residue intoluene (35 mL) was added t-BuONa (298 mg, 3.10 mmol, 3 eq) in portionat 0° C. under N₂. The mixture was warmed to 25° C. and stirred for 10min. The reaction mixture was diluted with ethyl acetate (20 mL) andadjusted PH to 8-9 with 2M HCl at 0° C., then extracted with ethylacetate (20 mL×2). The combined organic layers were washed with water(15 mL×1), dried over sodium sulfate, filtered and concentrated underreduced pressure to give a residue. The residue was purified by reversedphase flash [water (0.1% FA)/acetonitrile]. The desired fractions werecollected and neutralized with saturated NaHCO₃ solution (3 ml) andextracted with ethyl acetate (100 mL×2). The separated organic layer wasdried over sodium sulfate, filtered and concentrated under vacuum.Compound benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2R)-1-ethylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(350 mg, 526 umol, 51% yield, 97.1% purity) was obtained as a whitesolid. LCMS [ESI, M+1]: 646.

Step F:2-[(2S)-4-[2-[[(2R)-1-ethylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2R)-1-ethylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(305 mg, 472 umol, 1 eq) in MeOH (40 mL) and NH₃·MeOH (20 mL) was addedPd/C (300 mg, 10% purity) under N₂. The suspension was degassed undervacuum and purged with H₂ three times. The mixture was stirred under H₂(15 psi) at 25° C. for 0.5 hour. The reaction mixture was filtered andconcentrated under reduced pressure to give a residue. The crude productwas used to next step directly without further purification. Compound2-[(2S)-4-[2-[[(2R)-1-ethylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(240 mg, crude) was obtained as a green solid. LCMS [ESI, M+1]: 512.

Step G:2-[(2S)-4-[2-[[(2R)-1-ethylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a mixture of2-[(2S)-4-[2-[[(2R)-1-ethylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(240 mg, crude) in DCM (10 mL) was added TEA (237 mg, 2.35 mmol, 326uL), then prop-2-enoyl prop-2-enoate (59.2 mg, 469 umol) was added inportion at 0° C. under N₂. The mixture was warmed to 25° C. and stirredfor 0.5 hour. The reaction mixture was quenched by adding saturatedNaHCO₃ solution (2 mL) at 0° C., and then extracted with DCM mL (20mL×3). The combined organic layers were washed with brine (15 mL×1),dried over sodium sulfate, filtered and concentrated under reducedpressure to give a residue. The residue was purified by columnchromatography (Al₂O₃, Petroleum ether/Ethyl acetate=50/1 to Ethylacetate/Methanol=5/1) and further purified by prep-HPLC (column:Phenomenex Gemini 150*25 mm*10 um; mobile phase: [water (0.05% ammoniahydroxide v/v)-ACN]; B %: 59%-89%, 12 min). Title compound2-[(2S)-4-[2-[[(2R)-1-ethylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 334, 44.2 mg, 75.2 umol, two steps 16% yield, 96.4% purity) wasobtained as a white solid. LCMS [ESI, M+1]: 566.

¹H NMR (400 MHz, chloroform-d) δ=8.24-8.18 (m, 1H), 7.90-7.83 (m, 1H),7.62 (d, J=8.0 Hz, 1H), 7.54-7.48 (m, 2H), 7.44 (t, J=7.6 Hz, 1H), 7.15(d, J=7.6 Hz, 1H), 6.60 (br s, 1H), 6.47-6.35 (m, 1H), 5.84 (br d,J=10.4 Hz, 1H), 5.11 (br s, 1H), 4.39 (br d, J=8.4 Hz, 1H), 4.35-4.21(m, 2H), 4.19-4.09 (m, 2H), 4.02 (br d, J=12.4 Hz, 1H), 3.47 (br s, 2H),3.34 (br s, 2H), 3.26-3.07 (m, 3H), 3.05-2.63 (m, 5H), 2.44 (br dd,J=6.8, 12.0 Hz, 1H), 2.26 (br d, J=8.0 Hz, 1H), 2.12-1.94 (m, 1H), 1.80(br d, J=4.0 Hz, 4H), 1.15 (br t, J=7.2 Hz, 3H).

Example 335

2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S,4R)-1-ethyl-4-methoxy-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step 1: methyl (2S,4R)-methoxypyrrolidine-2-carboxylate. To a solutionof O1-tert-butyl-O2-methyl(2S,4R)-4-methoxypyrrolidine-1,2-dicarboxylate (5.00 g, 19.3 mmol, 1.0eq) in DCM (5.0 mL) was added TFA (7.70 g, 67.5 mmol, 5.0 mL, 3.50 eq).The mixture was stirred at 20° C. for 1 hour. After completion, themixture was concentrated. The product methyl(2S,4R)-4-methoxypyrrolidine-2-carboxylate (3.0 g, crude, TFA) wasobtained as yellow oil.

Step 2: methyl (2S,4R)-1-ethyl-4-methoxy-pyrrolidine-2-carboxylate. To asolution of methyl (2S,4R)-4-methoxypyrrolidine-2-carboxylate (3.0 g,11.0 mmol, 1.0 eq, TFA) and K₂CO₃ (4.55 g, 32.9 mmol, 3.0 eq) in MeCN(30.0 mL) was added iodoethane (1.71 g, 11.0 mmol, 878 uL, 1.0 eq) inportions. The mixture was stirred at 25° C. for 1 hour and heated to 78°C., then stirred at 78° C. for 11 hours. After completion, the mixturewas filtered and concentrated. The obtained product was purified bycolumn chromatography (SiO₂, PE:EA=10:1-EA:MeOH=10:1) to give methyl(2S,4R)-1-ethyl-4-methoxy-pyrrolidine-2-carboxylate (1.20 g, 6.41 mmol,two steps 33% yield) as yellow oil.

¹H NMR (400 MHz, Chloroform-d) δ 4.04-3.95 (m, 1H), 3.73 (s, 3H),3.55-3.33 (m, 2H), 3.29 (s, 3H), 2.83-2.70 (m, 1H), 2.53-2.35 (m, 2H),2.14 (dd, J=5.6, 8.0 Hz, 2H), 1.09 (t, J=7.2 Hz, 3H).

Step 3: [(2S,4R)-1-ethyl-4-methoxy-pyrrolidin-2-yl]methanol. To asolution of methyl (2S,4R)-1-ethyl-4-methoxy-pyrrolidine-2-carboxylate(1.20 g, 6.41 mmol, 1.0 eq) in THF (15.0 mL) was added LiAlH₄ (730 mg,19.2 mmol, 3.0 eq). The mixture was stirred at −78° C. for 1 hour. Aftercompletion, the mixture was quenched with saturated Na₂SO₄ aqueous (0.30mL) and filtered, washed with THF (10.0 mL). The mother liquid wasconcentrated. The obtained product was purified by column chromatography(SiO₂, PE:EA=10:1-EA:MeOH=5:1) to give[(2S,4R)-1-ethyl-4-methoxy-pyrrolidin-2-yl]methanol (600 mg, 3.77 mmol,59% yield) as yellow oil.

¹H NMR (400 MHz, Chloroform-d) δ 3.92-3.83 (m, 1H), 3.66 (dd, J=3.2,10.8 Hz, 1H), 3.49-3.35 (m, 2H), 3.30 (s, 3H), 2.89-2.76 (m, 2H),2.40-2.27 (m, 2H), 2.07-1.97 (m, 1H), 1.93-1.82 (m, 1H), 1.08 (t, J=7.2Hz, 3H).

Step A: tert-butyl(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[(2S,4R)-1-ethyl-4-methoxy-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.To a solution of [(2S,4R)-1-ethyl-4-methoxy-pyrrolidin-2-yl]methanol(266 mg, 1.67 mmol, 2.00 eq) in THF (5.0 mL) was added t-BuONa (241 mg,2.50 mmol, 3.0 eq). The mixture was stirred at 0° C. for 0.5 hour. Thentert-butyl(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(500 mg, 835 umol, 1.0 eq) was added to the above liquid. Afteraddition, the mixture was stirred at 0° C. for 0.5 hour. Uponcompletion, the mixture was added water (10.0 mL) and extracted withethyl acetate (10.0 mL×3). The organic layer was dried over Na₂SO₄,filtered and concentrated. The obtained product was purified by columnchromatography (SiO₂, PE:EA=20:1-EA:MeOH=10:1) to give tert-butyl(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S,4R)-1-ethyl-4-methoxy-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(440 mg, 513 umol, 62% yield, 81% purity) as yellow solid. LCMS [ESI,M+1]: 694.

¹H NMR (400 MHz, Chloroform-d) δ 7.41 (t, J=8.0 Hz, 1H), 7.28 (d, J=8.0Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 4.63 (br s, 1H), 4.42 (br dd, J=4.4,10.8 Hz, 1H), 4.18-4.06 (m, 4H), 4.06-3.96 (m, 2H), 4.06-3.96 (m, 1H),3.92-3.86 (m, 1H), 3.36-3.20 (m, 6H), 3.18-2.96 (m, 4H), 2.94-2.66 (m,4H), 2.58-2.39 (m, 1H), 2.37-2.30 (m, 1H), 2.14-2.07 (m, 1H), 2.02-1.91(m, 1H), 1.53 (s, 9H), 1.13 (t, J=7.4 Hz, 3H).

Step B:2[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S,4R)-1-ethyl-4-methoxy-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl (2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S,4R)-1-ethyl-4-methoxy-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(390 mg, 455 umol, 1.0 eq) in DCM (1.00 mL) was added TFA (1.54 g, 13.5mmol, 1.0 mL, 29.7 eq). The mixture was stirred at 25° C. for 10minutes. After completion, the mixture was concentrated under vacuum.The product2[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S,4R)-1-ethyl-4-methoxy-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(400 mg, crude, 2 TFA) was obtained as yellow oil. LCMS [ESI, M+1]: 594.

Step C:2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S,4R)-1-ethyl-4-methoxy-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S,4R)-1-ethyl-4-methoxy-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(400 mg, 487 umol, 1.0 eq, 2 TFA) in DCM (2.0 mL) was added DIEA (629mg, 4.87 mmol, 847 uL, 10.0 eq) at −30° C. Then prop-2-enoylprop-2-enoate (92.0 mg, 730 umol, 1.50 eq) was added to the above liquidat −30° C. and the mixture was stirred at −30° C. for 0.5 hour. Aftercompletion, the mixture was quenched with MeOH (0.50 mL) andconcentrated under vacuum. The title compound was purified by prep-HPLC(column: Phenomenex Gemini 150*25 mm*10 um; mobile phase: [water (0.05%ammonia hydroxide v/v)-ACN]; B %: 50%-80%, 12 min) to give2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S,4R)-1-ethyl-4-methoxy-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 335, 120 mg, 182 umol, two steps 28% yield, 99% purity) aswhite solid. LCMS [ESI, M+1]: 648.

¹H NMR (400 MHz, Chloroform-d) δ 7.42 (t, J=8.0 Hz, 1H), 7.29 (d, J=6.4Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 6.68-6.55 (m, 1H), 6.42 (dd, J=1.6,16.4 Hz 1H), 5.85 (br d, J=10.8 Hz, 1H), 5.20-4.51 (m, 1H), 4.42 (dd,J=4.4, 10.8 Hz, 1H), 4.19-4.04 (m, 4H), 4.04-3.72 (m, 3H), 3.70-3.41 (m,2H), 3.39-3.22 (m, 5H), 3.20-2.79 (m, 7H), 2.76 (br s, 1H), 2.50-2.40(m, 1H), 2.33 (dd, J=5.2, 10.0 Hz, 1H), 2.15-2.05 (m, 1H), 2.03-1.90 (m,1H), 1.13 (t, J=7.2 Hz, 3H).

Example 336

1-[(2R,5S)-4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2,5-dimethyl-piperazin-1-yl]prop-2-en-1-one

Step A: tert-butyl(2R,5S)-4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-2,5-dimethyl-piperazine-1-carboxylate.A solution of7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (2.70 g,9.18 mmol, 1.00 eq), tort-butyl(2R,5S)-2,5-dimethylpiperazine-1-carboxylate (1.77 g 8.26 mmol, 0.90 eq)and DIEA (2.37 g 18.4 mmol, 3.20 mL, 2.00 eq) in NMP (30.0 mL) wasstirred at 100° C. for 7 hours. The mixture was diluted with ethylacetate (50.0 mL), washed with brine (3×100 mL). The organic layer wasdried over Na₂SO₄, filtered and concentrated under vacuum. The residuewas purified by column chromatography (SiO₂ petroleum ether/ethylacetate=3/1) to give tert-butyl(2R,5S)-4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-2,5-dimethyl-piperazine-1-carboxylate(2.80 g, 5.69 mmol, 62% yield) as a yellow solid. LCMS [ESI, M+1]: 472.

¹H NMR (400 MHz, chloroform-d) δ=7.40-7.29 (m, 5H), 4.45-4.19 (m, 2H),3.71-3.61 (m, 4H), 3.54-3.43 (m, 3H), 3.41-3.36 (m, 1H), 2.81-2.67 (m,2H), 2.64-2.49 (m, 2H), 1.48 (s, 9H), 1.20 (d, J=6.8 Hz, 3H), 1.17 (d,J=6.81 Hz, 3H).

Step B: tert-butyl(2R,5S)-4-[7-benzyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2,5-dimethyl-piperazine-1-carboxylate.To a solution of [(2S)-1-methylpyrrolidin-2-yl]methanol (854 mg, 7.41mmol, 880 uL, 2.50 eq) in THF (20.0 mL) was added NaH (237 mg, 5.93mmol, 60.0% purity, 2.00 eq) at 0° C. After stirred at 0° C. for 0.5 h,tert-butyl (2R,5S)-4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-2,5-dimethyl-piperazine-1-carboxylate(1.40 g, 2.97 mmol, 1.00 eq) was added. The mixture was stirred at 80°C. for 4 hours. The mixture was diluted with water (20.0 mL), extractedwith ethyl acetate (3×30.0 mL), the organic layer was washed with brine(1×40.0 mL), dried over Na₂SO₄, filtered and concentrated under vacuum.The residue was purified by column chromatography (Al₂O₃, methanol/ethylacetate 1/10) to give tert-butyl(2R,5S)-4-[7-benzyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2,5-dimethyl-piperazine-1-carboxylate(1.55 g, 2.56 mmol, 86% yield) as a yellow solid. LCMS [ESI, M+1]: 551.

¹H NMR (400 MHz, chloroform-d) δ=7.39-7.28 (m, 5H), 4.31 (br dd, J=4.8,10.4 Hz, 2H), 4.16-4.08 (m, 1H), 3.72-3.62 (m, 4H), 3.61-3.56 (m, 1H),3.52-3.43 (m, 2H), 3.38 (br s, 1H), 3.08 (br t, J=8.0 Hz, 1H), 2.81-2.48(m, 6H), 2.45 (s, 3H), 2.33-2.20 (m, 1H), 2.04-1.95 (m, 1H), 1.78-1.65(m, 3H), 1.48 (s, 9H), 1.17 (br d, J=6.4 Hz, 6H).

Step C: tert-butyl(2R,5S)-2,5-dimethyl-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.NH₃ was bubbled in methanol (150 mL) at −78° C. for 15 mins. tert-Butyl(2R,5S)-4-[7-benzyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2,5-dimethyl-piperazine-1-carboxylate(2.80 g, 5.08 mmol, 1.00 eq) and Pd/C (0.50 g, 10.0% purity) was addedinto the mixture. After stirred at 40° C. for 5 hours under H₂ at 15psi, the mixture was filtered and concentrated under vacuum to givetert-butyl(2R,5S)-2,5-dimethyl-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(2.20 g, crude) as a yellow oil and used into next step without furtherpurification. LCMS [ESI, M+1]: 461.

Step D: tert-butyl(2R,5S)-4-[7-(3-benzyloxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2,5-dimethyl-piperazine-1-carboxylate.A mixture of tert-butyl(2R,5S)-2,5-dimethyl-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1.00 g, crude), 3-benzyloxy-1-bromo-naphthalene (1.02 g, 3.26 mmol,1.50 eq), RuPhos (203 mg, 434 umol), Pd₂(dba)₃ (199 mg, 217 umol) andCs₂CO₃ (2.12 g, 6.51 mmol) in toluene (30.0 mL) was stirred at 110° C.for 5 hours under N₂. The mixture was diluted with water (20.0 mL),extracted with ethyl acetate (3×40.0 mL). The organic layer was washedwith brine (1×50.0 mL), dried over Na₂SO₄, filtered and concentratedunder vacuum. The residue was purified by reversed phase flash [water(TFA, 0.10%)/acetonitrile]. The desired fraction was collected andadjusted pH>7 by saturated sodium bicarbonate (5.00 mL), and thenextracted with ethyl acetate (3×30.0 mL). The organic layer was washedwith brine (1×30.0 mL), dried over Na₂SO₄, filtered and concentratedunder vacuum to give tert-butyl(2R,5S)-4-[7-(3-benzyloxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2,5-dimethyl-piperazine-1-carboxylate(1.06 g, 1.47 mmol, two steps 68% yield) as a yellow solid. LCMS [ESI,M/2+1]: 347.

¹H NMR (400 MHz, chloroform-d) δ=8.11 (d, J=8.4 Hz, 1H), 7.77-7.71 (m,1H), 7.52-7.40 (m, 5H), 7.39-7.33 (m, 2H), 6.99 (d, J=2.0 Hz, 1H), 6.90(d, J=2.0 Hz, 1H), 5.18 (s, 2H), 4.48-4.42 (m, 1H), 4.38 (dd, J=4.8,10.4 Hz, 1H), 4.32-4.25 (m, 1H), 4.20 (br d, J=5.6 Hz, 1H), 4.16-4.09(m, 1H), 3.76 (br s, 1H), 3.70-3.61 (m, 1H), 3.60-3.52 (m, 1H), 3.45 (brs, 2H), 3.24 (br s, 1H), 3.10 (br t, J=7.6 Hz, 1H), 2.93 (br s, 1H),2.80-2.61 (m, 2H), 2.49 (s, 3H), 2.33-2.25 (m, 1H), 2.12-2.03 (m, 1H),1.91-1.76 (m, 4H), 1.50 (s, 9H), 1.27-1.22 (m, 6H).

Step E: tert-butyl(2R,5S)-4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2,5-dimethyl-piperazine-1-carboxylate.A mixture of tert-butyl(2R,5S)-4-[7-(3-benzyloxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2,5-dimethyl-piperazine-1-carboxylate(0.90 g, 1.30 mmol, 1.00 eq) and Pd/C (0.10 g, 10.0% purity) in methanol(40.0 mL) was stirred at 25° C. for 1 hour under H₂ at 15 psi. Themixture was filtered and concentrated under vacuum to give tert-butyl(2R,5S)-4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2,5-dimethyl-piperazine-1-carboxylate(0.72 g, crude) as a yellow solid which was used into next step withoutfurther purification. LCMS [ESI, M+1]: 603.

Step F:4-[4-[(2S,5R)-2,5-dimethylpiperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol.A mixture of tert-butyl(2R,5S)-4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2,5-dimethyl-piperazine-1-carboxylate(0.70 g, crude) and TFA (1.99 g, 17.42 mmol, 1.29 mL) in dichloromethane(1.20 mL) was stirred at 25° C. for 0.5 h. The mixture was concentratedunder vacuum to give4-[4-[(2S,5R)-2,5-dimethylpiperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol(849 mg, crude, 2TFA) as a yellow oil and used into next step withoutfurther purification. LCMS [ESI, M+1]: 503.

Step G:1-[(2R,5S)-4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2,5-dimethyl-piperazin-1-yl]prop-2-en-1-one.To a solution of4-[4-[(2S,5R)-2,5-dimethylpiperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol(0.84 g crude, 2TFA) and TEA (1.16 g, 11.5 mmol, 1.60 mL) indichloromethane (3.00 mL) was added prop-2-enoyl prop-2-enoate (102 mg,805 umol) at −40° C. After stirred at −40° C. for 0.5 h, the mixture wasquenched with water (0.10 mL) and concentrated under vacuum. The residuewas purified by reversed phase flash [water (0.1% TFA)-acetonitrile] andprep-HPLC (column: Phenomnenex Luna Phenyl-Hexyl 150_30_5 um; mobilephase: [water (10 mM NH₄HCO₃)-ACN]; B %: 45%-75%, 3 min). The desiredfraction was collected and lyophilized to give title compound1-[(2R,5S)-4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2,5-dimethyl-piperazin-1-yl]prop-2-en-1-one(EXAMPLE 336, 55.8 mg, 94.1 umol, three steps 8.2% yield, 93.9% purity)as a off-white solid. LCMS [ESI, M+1]:557.

SFC: “Column: Chiralpak AS-3 50×4.6 mm I.D., 3 um, Mobile phase:methanol (0.05% DEA) in CO₂ from 5% to 40%, Flow rate: 3 mL/min,Wavelength: 220 nm”.

¹H NMR (400 MHz, chloroform-d) δ=7.97 (br d, J=8.0 Hz, 1H), 7.63 (d,J=8.0 Hz, 1H), 7.40-7.34 (m, 1H), 7.26 (dt, J=1.6, 8.4 Hz, 1H), 6.90 (d,J=1.6 Hz, 1H), 6.65 (br s, 1H), 6.61-6.43 (m, 1H), 6.39-6.26 (m, 1H),5.73 (br t, J=8.8 Hz, 1H), 4.83 (br s, 1H), 4.55 (br d, J=5.6 Hz, 1H),4.43-4.04 (m, 4H), 3.91 (br d, J=17.2 Hz, 1H), 3.77-3.26 (m, 5H), 3.19(br t, J=8.0 Hz, 1H), 3.06-2.68 (m, 3H), 2.63 (br s, 3H), 2.57 (br d,J=13.2 Hz, 1H), 2.41-2.33 (m, 1H), 2.15-1.83 (m, 4H), 1.11-0.96 (m, 6H).

Example 337

2-[(2S)-4-[7-(3-chloro-2-ethyl-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step 1: 1-(2-bromo-6-chloro-phenyl) ethanol. Into a flame-dried 100 mLround-bottom flask equipped with a magnetic stir bar and under N₂ wasadded 2-bromo-6-chloro-benzaldehyde (10.0 g, 45.6 mmol, 1 eq) and THF(100 mL). The mixture was cooled to 0° C. and then MeMgBr (3 M in Et₂O,22.8 mL, 1.5 eq) was added dropwise over 20 min. The resultingsuspension was stirred at 0° C. for 2 h. The reaction mixture wasquenched by dropwise addition of a saturated aqueous NH₄Cl solution (10mL). The mixture was cooled, poured into a 100 mL separatory funnelcontaining water (150 mL) and the mixture was extracted with ethylacetate (2×150 mL). The combined organic layers were washed with brine,dried over MgSO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (Petroleum ether/Ethylacetate=100/1 to 10/1). Compound 1-(2-bromo-6-chloro-phenyl) ethanol(8.00 g, 32.6 mmol, 72% yield, 96% purity) was obtained as a yellow oil.LCMS [ESI, M−17]: 219.

¹H NMR (400 MHz, chloroform-d) δ=7.46 (br d, J=8.0 Hz, 1H), 7.31 (br d,J=8.0 Hz, 1H), 7.07-6.96 (m, 1H), 5.68-5.44 (m, 1H), 3.24 (br d, J=8.0Hz, 1H), 1.61 (d, J=4.4 Hz, 3H).

Step 2: 1-bromo-3-chloro-2-ethyl-benzene. To a mixture of1-(2-bromo-6-chloro-phenyl)ethanol (8.00 g, 34.0 mmol, 1 eq) in DCE (150mL) was added BF₃·Et₂O (14.5 g, 102 mmol, 12.6 mL, 3 eq) and Et₃SiH(19.8 g, 170 mmol, 27.1 mL, 5 eq) in portions at 0° C. The mixture wasstirred at 50° C. for 6 hours. The reaction mixture was washed withsaturated NaHCO₃ aqueous (2×75 mL) and saturated brine (1×75 mL), thendried over Na₂SO₄, filtered and concentrated under vacuum. The residuewas purified by silica gel chromatography (Petroleum ether). The residuewas purified by prep-HPLC (column: Phenomenex Synergi Max-RP 250*50mm*10 um; mobile phase: [water (0.225% FA)-ACN]; B %: 65 ACN %-95 ACN %,30 min; 60% min). Compound 1-bromo-3-chloro-2-ethyl-benzene (1.50 g,6.83 mmol, 20% yield, 100% purity) was obtained as a yellow oil.

Step A: tert-butyl(2S)-4-[7-(3-chloro-2-ethyl-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.To a mixture of tert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(Intermediate 66, 300 mg, 636 umol, 1 eq),1-bromo-3-chloro-2-ethyl-benzene (279 mg, 1.27 mmol, 2 eq), Pd₂(dba)₃(117 mg, 127 umol, 0.2 eq), RuPhos (89.1 mg, 191 umol, 0.3 eq) andCs₂CO₃ (622 mg, 1.91 μmol, 3 eq) in toluene (30 mL) was degassed andpurged with N₂ for 3 times, and then the mixture was stirred at 90° C.for 6 hours under N₂ atmosphere. The reaction mixture was added H₂O(1×200 mL) and Ethyl acetate (1×250 mL). The organic phase wasseparated, washed with brine (1×200 mL), dried over sodium sulfate,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by reversed phase flash [water (0.1%FA)/acetonitrile]. The desired fractions were collected and neutralizedto pH=7 with saturated NaHCO₃ solution and extracted with ethyl acetate(1×200 mL). The separated organic layer was dried over sodium sulfate,filtered and concentrated under vacuum. tert-butyl(2S)-4-[7-(3-chloro-2-ethyl-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(155 mg, 0.254 mmol, 100% purity, 40% yield) was obtained as a yellowsolid. LCMS [ESI, M+1]: 610.

¹H NMR (400 MHz, chloroform-d) δ=7.20-7.16 (m, 1H), 7.13 (t, J=8.0 Hz,1H), 7.07-7.03 (m, 1H), 4.61 (br s, 1H), 4.39 (dd, J=5.2, 10.6 Hz, 1H),4.16 (dd, J=6.8, 10.4 Hz, 1H), 4.09-3.95 (m, 4H), 3.91 (br d, J=13.2 Hz,1H), 3.26 (dd, J=3.6, 13.7 Hz, 1H), 3.22-2.96 (m, 5H), 2.90 (q, J=7.4Hz, 2H), 2.84-2.63 (m, 5H), 2.48 (s, 3H), 2.35-2.23 (m, 1H), 2.13-2.00(m, 1H), 1.83-1.70 (m, 3H), 1.52 (s, 9H), 1.22 (t, J=7.4 Hz, 3H).

Step B:2-[(2S)-4-[7-(3-chloro-2-ethyl-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-4-[7-(3-chloro-2-ethyl-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(310 mg, 508 umol, 1 eq) in DCM (600 uL) was added TFA (869 mg, 7.62mmol, 564 uL, 15 eq) at 0° C. under nitrogen atmosphere. The mixture wasstirred at 25° C. for 1 h. After that, the mixture was concentratedunder vacuum.2-[(2S)-4-[7-(3-chloro-2-ethyl-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(850 mg, crude, 2 TFA) was obtained as a yellow oil. LCMS [EST, M+1]:510.

Step C:2-[(2S)-4-[7-(3-chloro-2-ethyl-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a mixture of2-[(2S)-4-[7-(3-chloro-2-ethyl-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(850 mg, crude, 2 TFA) and prop-2-enoyl chloride (59.8 mg, 660 umol,53.8 uL) in DCM (8 mL) was added TEA (514 mg, 5.08 mmol, 707 uL) inportion. The mixture was stirred at −40° C. for 30 min. The reactionmixture was quenched by NaHCO₃ saturated solution (2 mL) at 0° C., andthen extracted with CH₂Cl₂ (2×30 mL). The combined organic layers werewashed with brine (1×30 mL), dried over sodium sulfate, filtered andconcentrated under vacuum to give a residue. The residue was purified bycolumn chromatography (Al₂O₃; Ethyl acetate/Methanol=20/1 to 3/1). Theresidue was purified by prep-HPLC (column: Gemini 150*25 5 u; mobilephase: [water (0.04% NH₃·H₂O)-ACN]; B %: 65%-95%, 10 min). Titlecompound2-[(2S)-4-[7-(3-chloro-2-ethyl-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 337, 142 mg, 252 umol, two steps 50% yield, 100% purity) wasobtained as a white solid. LCMS [ESI, M+1]: 564.

SFC condition: “Column: Chiralpak AD-3 100×4.6 mm I.D., 3 um, Mobilephase: methanol (0.05% DEA) in CO₂ from 5% to 40%, Flow rate: 3 mL/min,Wavelength: 220 nm”.

¹H NMR (400 MHz, dmso-d₆) δ=7.21 (s, 3H), 6.78 (dd, J=10.4, 16.8 Hz,1H), 6.15 (dd, J=2.0, 16.8 Hz, 1H), 5.74 (dd, J=2.0, 10.6 Hz, 1H), 4.84(br s, 1H), 4.28 (dd, J=5.2, 10.8 Hz, 1H), 4.23-4.07 (m, 2H), 4.05-3.90(m, 4H), 3.39 (br s, 1H), 3.27 (br dd, J=3.6, 13.6 Hz, 1H), 3.20-3.05(m, 3H), 2.99-2.93 (m, 2H), 2.93-2.76 (m, 41H), 2.61-2.52 (m, 2H),2.40-2.31 (m, 3H), 2.22 (q, J=8.4 Hz, 1H), 2.00-1.87 (m, 1H), 1.77-1.54(m, 3H), 1.19 (t, J=7.2 Hz, 3H).

Example 338

2-((S)-1-acryloyl-4-(7-(8-fluoronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Insert: 1-bromo-8-fluoro-naphthalene. To a solution of1,8-dibromonaphthalene (2 g, 6.99 mmol, 1 eq) in THF (50 mL) was addedn-BuLi (2.5 M in hexane, 4.20 mL, 1.5 eq) at −78° C. dropwise. Afterstirring for 10 minutes at −78° C., a solution ofN-(benzenesulfonyl)-N-fluoro-benzenesulfonamide (4.41 g, 13.9 mmol, 2eq) in THF (10 mL) was added dropwise. The mixture was warmed up to 25°C. and stirred for 3 hours. The reaction mixture was quenched with water(10 mL) and extracted with ethyl acetate (30 mL×3). The combined organiclayers were washed with brine (50 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by prep-HPLC (column: Phenomenex Synergi Max-RP 250*50 mm*10um; mobile phase: [water (0.225% FA)-ACN]; B %: 50%-75%, 25 min). Themixture was adjusted pH=7 by addition saturated NaHCO₃ aqueous solutionand extracted with ethyl acetate (50 mL×3). The combined organic layerswere washed with brine (20 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. 1-bromo-8-fluoro-naphthalene (560mg, 2.46 mmol, 35% yield, 99% purity) was obtained as a yellow solid.

¹H NMR (400 MHz, chloroform-d) δ=7.81 (d, J=7.2 Hz, 2H), 7.66 (d, J=8.4Hz, 1H), 7.49-7.39 (m, 1H), 7.31 (t, J=7.6 Hz, 1H), 7.23 (td, J=0.8, 5.2Hz, 1H).

Step A: tert-butyl(2S)-2-(cyanomethyl)-4-[7-(8-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.A mixture of 1-bromo-8-fluoro-naphthalene (310 mg, 1.38 mmol, 1.3 eq),tert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(Intermediate 66, 500 mg, 1.06 mmol, 1 eq), Cs₂CO₃ (863 mg, 2.65 mmol,2.5 eq), RuPhos (98.9 mg, 212 umol, 0.2 eq) and Pd₂(dba)₃ (194 mg, 212umol, 0.2 eq) in toluene (10 mL) was degassed and purged with N₂ for 3times, and then the mixture was stirred at 100° C. for 3 hours under N₂atmosphere. The reaction mixture was diluted with water (20 mL) andextracted with ethyl acetate (20 mL×3). The combined organic layers werewashed with brine (20 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give a residue. The residue was purified byreversed phase flash [water (0.1% formic acid)/acetonitrile)]. Thedesired fractions were adjusted pH=7 with saturated NaHCO₃ aqueoussolution and extracted with ethyl acetate (20 mL×3). The combinedorganic layers were washed with brine (20 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure. Compound tert-butyl(2S)-2-(cyanomethyl)-4-[7-(8-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(370 mg, 570 umol, 54% yield, 95% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 616.

¹H NMR (400 MHz, chloroform-d) δ=7.64 (d, J=7.6 Hz, 1H), 7.56 (br d,J=8.8 Hz, 1H), 7.47-7.42 (m, 1H), 7.20-7.08 (m, 3H), 4.64 (br s, 1H),4.47-4.27 (m, 2H), 4.23-4.14 (m, 2H), 4.11-3.82 (m, 3H), 3.81-3.65 (m,1H), 3.44-3.23 (m, 2H), 3.19-3.07 (m, 2H), 3.02-2.79 (m, 3H), 2.77-2.66(m, 2H), 2.56 (br s, 1H), 2.50 (s, 3H), 2.34-2.25 (m, 1H), 2.13-2.06 (m,1H), 1.82-1.72 (m, 3H), 1.53 (s, 9H).

Step B:2-[(2S)-4-[7-(8-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-2-(cyanomethyl)-4-[7-(8-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(370 mg, 600 umol, 1 eq) in DCM (600 uL) was added TFA (1.03 g, 9.01mmol, 667 uL, 15 eq). The mixture was stirred at 25° C. for 1 hour. Thereaction mixture was concentrated under vacuum. Compound2-[(2S)-4-[7-(8-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(378 mg, 600 umol, 99% yield, TFA) was obtained as a yellow oil and usednext step directly without purification. LCMS [ESI, M+1]: 516.

Step C:2-[(2S)-4-[7-(8-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(261 mg, 506 umol, 1 eq, TFA) in DCM (5 mL) was added TEA (512 mg, 5.07mmol, 705 uL, 10 eq) at 0° C. After addition, and prop-2-enoylprop-2-enoate (51.1 mg, 405 umol, 0.8 eq) in DCM (1 mL) was addeddropwise at 0° C. After stirred at 25° C. for 1 hour, the reactionmixture was quenched with saturated NaHCO₃ aqueous solution (1 mL) andextracted with ethyl acetate (20 mL×3). The combined organic layers werewashed with brine (20 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give a residue. The residue was purified byprep-HPLC (column: Phenomenex Gemini 150*25 mm*10 um; mobile phase:[water (0.05% ammonia hydroxide v/v)-ACN]; B %: 48%-78%, 12 min). Titlecompound2-[(2S)-4-[7-(8-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 338, 93.5 mg, 163 umol, 32% yield, 99.4% purity) was obtainedas a white solid. LCMS [ESI, M+1]: 570.

SFC condition: “OD-3_MeOH (DEA)_40_3 mL-35T Column: Chiralcel OD-350×4.6 mm I.D., 3 um Mobile phase: 40% methanol (0.05% DEA) in CO₂ Flowrate: 3 mL/min Wavelength: 220 nm”.

¹H NMR (400 MHz, chloroform-d) δ=7.64 (d, J=8.0 Hz, 1H), 7.56 (d, J=8.4Hz, 1H), 7.47-7.35 (m, 2H), 7.19-7.09 (m, 2H), 6.60 (br s, 1H), 6.40(dd, J=1.6, 16.8 Hz, 1H), 5.83 (br d, J=: 10.4 Hz, 1H), 5.30-4.48 (m,1H), 4.46-4.28 (m, 2H), 4.27-3.85 (m, 5H), 3.73 (br s, 1H), 3.56-2.54(m, 10H), 2.49 (s, 3H), 2.37-2.21 (m, 1H), 2.12-1.97 (m, 1H), 1.95-1.79(m, 3H).

Example 339

2-((S)-1-acryloyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-(((S)-1-ethylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: tert-butyl (2S)-2-(benzyloxymethyl)pyrrolidine-1-carboxylate. Toa solution of NaH (1.19 g, 49.6 mmol, 2.0 eq) in THF (50.0 mL) was addeda solution of tert-butyl (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate(5.00 g, 24.8 mmol, 1.0 eq) in THF (50.0 mL) at 0° C. and the mixturewas stirred at 10° C. for 1 hour. Bromomethylbenzene (6.38 g, 37.3 mmol,4.43 mL, 1.50 eq) was added dropwise to the above mixture at 0° C. andthe mixture was stirred at 10° C. for 16 hours. After completion, themixture was quenched with saturated NH₄Cl aqueous (20.0 mL) and dilutedwith ethyl acetate (50.0 ml). The separated organic layer was washedwith brine (1×30.0 mL) and dried over sodium sulfate, filtered andconcentrated under vacuum. The obtained product was purified by columnchromatography (SiO₂, Petroleum ether:Ethyl acetate=10:1-3:1) to givetert-butyl (2S)-2-(benzyloxymethyl)pyrrolidine-1-carboxylate (6.60 g,10.4 mmol, 42% yield) as yellow oil.

¹H NMR (400 MHz, Methanol-d₄) δ 7.44-7.26 (m, 5H), 4.53 (s, 2H),4.00-3.85 (m, 1H), 3.61-3.39 (m, 2H), 3.38-3.33 (m, 2H), 2.04-1.77 (m,4H), 1.50-1.36 (m, 9H).

Step B: (2S)-2-(benzyloxymethyl)pyrrolidine. To a solution of tert-butyl(2S)-2-(benzyloxymethyl)pyrrolidine-1-carboxylate (6.60 g, 22.7 mmol,1.0 eq) in DCM (23.0 mL) was added TFA (34.7 g, 304 mmol, 22.5 mL, 13.4eq) dropwise at 0° C. under nitrogen atmosphere. The mixture was stirredat 15° C. for 1 hour. After completion, the mixture was concentratedunder vacuum to give (2S)-2-(benzyloxymethyl)pyrrolidine (10.0 g, crude,TFA) as yellow oil. LCMS [ESI, M+1]: 192.

Step C: (2S)-2-(benzyloxymethyl)-1-ethylpyrrolidine. To a solution of(2S)-2-(benzyloxymethyl)pyrrolidine (2.0 g, 6.55 mmol, 1.0 eq, TFA) andacetaldehyde (1.44 g, 32.8 mmol, 1.84 mL, 5.0 eq) in MeOH (30.0 mL) wasadded CH₃COOH (787 mg, 13.1 mmol, 749 uL, 2.0 eq) and NaBH₃CN (1.65 g,26.2 mmol, 4.0 eq). The mixture was stirred at 20° C. for 2 hours. Aftercompletion, the pH was adjusted to 3 with 1 M HCl aqueous (15.0 mL) andconcentrated under vacuum to remove MeOH. The mixture was extracted withmixed solvent (PE/EA=10:1, 2×60.0 mL). The aqueous phase was adjusted tothe pH˜9 with saturated Na₂CO₃ aqueous (10.0 mL) and extracted withmixed solvent (EA/MeOH=10:1, 4×60.0 mL). The organic layers were driedover Na₂SO₄ and concentrated under vacuum. The obtained product waspurified by reversed-phase flash (0.1% TFA condition) to give(2S)-2-(benzyloxymethyl)-1-ethyl pyrolidine (707 mg, 3.18 mmol, 49%yield, 99.0% purity) as colorless oil.

¹H NMR (400 MHz, Chloroform-d) δ 7.36-7.31 (m, 4H), 7.31-7.26 (m, 1H),4.58-4.54 (s, 2H), 3.52 (dd, J=4.8, 9.2 Hz, 1H), 3.37 (dd, J=6.4, 9.2Hz, 1H), 3.20-3.12 (m, 1H), 3.01-2.89 (m, 1H), 2.66-2.58 (m, 1H),2.35-2.25 (m, 1H), 2.21-2.05 (m, 1H), 2.03-1.87 (m, 1H), 1.83-1.62 (m,3H), 1.11 (t, J=7.2 Hz, 3H).

Step D: [(2S)-1-ethylpyrrolidin-2-yl]methanol. To a solution of(2S)-2-(benzyloxymethyl)-1-ethyl-pyrrolidine (860 mg, 3.92 mmol, 1.00eq) in MeOH (3.00 mL) was added HCl·MeOH (4 M, 0.80 mL) and Pd(OH)₂/C(300 mg, 20% purity). The suspension was degassed under vacuum andpurged with H₂ several times. The mixture was stirred under H₂ (50 Psi)at 25° C. for 16 hours. After completion, the mixture was filtered andconcentrated. The product [(2S)-1-ethylpyrrolidin-2-yl]methanol (460 mg,3.56 mmol, 91% yield) was obtained as white solid. LCMS [ESI, M+1]: 130.

Step E: tert-butyl(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-ethylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.To a solution of tert-butyl(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(400 mg, 668 umol, 1.0 eq) and [(2S)-1-ethylpyrrolidin-2-yl]methanol(173 mg, 1.34 mmol, 2.0 eq) in toluene (8.0 mL) was added t-BuONa (128mg, 1.34 mmol, 2.0 eq) at 0° C., the reaction was stirred at 0° C. for0.5 hour. After completion, the reaction mixture was added water (30.0mL), then extracted with EA (2×20.0 mL), the combined organic layer waswashed with saturated brine (1×30.0 mL), then dried over Na₂SO₄,filtered and concentrated. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=5/1 to Ethylacetate/Methanol=20/1) to give tert-butyl(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-ethylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(240 mg, 353 umol, 53% yield, 97.6% purity) as light yellow solid. LCMS[ESI, M+1]: 664.

Step F: 2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-ethylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-ethylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(240 mg, 361 umol, 1.0 eq) in DCM (2.0 mL) was added TFA (3.08 g, 27.0mmol, 2.0 mL, 74.8 eq), the mixture was stirred at 20° C. for 0.5 hour.After completion, the reaction mixture was concentrated to give2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-ethylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(280 mg, crude, 2TFA) as yellow oil which was used for the next stepwithout further purification. LCMS [ESI, M+1]: 564.

Step G:2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-ethylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a mixture of2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-ethylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(280 mg, 496 umol, 1.0 eq, 2TFA) in DCM (5.0 mL) was added DIEA (642 mg,4.96 mmol, 865 uL, 10.0 eq) and prop-2-enoyl prop-2-enoate (62.6 mg, 496umol, 1.0 eq) at 0° C., the reaction mixture was stirred at 20° C. for0.5 hour. After completion, the reaction mixture was quenched with MeOH(5.0 mL), and concentrated. The residue was purified by columnchromatography (Base Al₂O₃, Ethyl acetate/Methanol=20/1), then the crudeproduct was concentrated and re-purified by prep-HPLC ((column:Phenomenex Gemini 150*25 mm*10 um; mobile phase: [water (0.05% ammoniahydroxide v/v)-ACN]; B %: 55%-85%, 12 min), the obtained product wasconcentrated, and then under lyophilization. The title compound2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-ethylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 339, 31.9 mg, 50.2 umol, 10% yield, 97.2% purity) was obtainedas yellow solid. LCMS [ESI, M+1]: 618.

¹H NMR (400 MHz, Chloroform-d) δ 7.37-7.29 (m, 1H), 7.23-7.18 (m, 1H),7.11 (d, J=8.0 Hz, 1H), 6.58-6.46 (m, 1H), 6.32 (dd, J=0.8, 16.4 Hz,1H), 5.76 (br d, J=10.4 Hz, 1H), 5.11-4.37 (m, 1H), 4.28 (dd, J=4.8,10.4 Hz, 1H), 4.09-3.96 (m, 4H), 3.89 (br d, J=12.4 Hz, 2H), 3.69-3.41(m, 1H), 3.33-2.51 (m, 12H), 2.38-2.28 (m, 1H), 2.20-2.11 (m, 1H),2.00-1.80 (m, 3H), 1.06 (t, J=7.2 Hz, 3H).

Example 340

2-((S)-1-acryloyl-4-(7-(4-methoxypyridin-3-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: tert-butyl(2S)-2-(cyanomethyl)-4-[7-(4-methoxy-3-pyridyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.A mixture of tert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(580 mg, 1.23 mmol, 1.0 eq), 3-bromo-4-methoxy-pyridine (694 mg, 3.69mmol, 3.0 eq), Pd₂(dba)₃ (113 mg, 123 umol, 0.1 eq), RuPhos (115 mg, 246umol, 0.2 eq) and Cs₂CO₃ (1.20 g, 3.69 mmol, 3.0 eq) in toluene (25.0mL) was degassed and purged with N₂ for 3 times, and then the mixturewas stirred at 90° C. for 6 hours under N₂ atmosphere. After completion,the organic solvent was removed under vacuum, and washed with water(20.0 mL). The aqueous phase was extracted with ethyl acetate (2×30.0mL). Combined extracts were washed with brine (100 mL), dried overNa₂SO₄, the solvent was then removed under vacuum. The residue waspurified by reversed phase flash HPLC [C18, 0.1% FA in water, 0-70%MeCN]. The obtained product was adjusted with saturated NaHCO₃ aqueousto pH˜8, then concentrated, the aqueous was extracted with ethyl acetate(2×50.0 mL), the combined organic layer was dried over Na₂SO₄, filteredand concentrated. Compound tert-butyl(2S)-2-(cyanomethyl)-4-[7-(4-methoxy-3-pyridyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(230 mg, 397 umol, 32% yield, 100% purity) was obtained as yellow solid.LCMS [ESI, M+1]: 579.

Step B:2-[(2S)-4-[7-(4-methoxy-3-pyridyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-2-(cyanomethyl)-4-[7-(4-methoxy-3-pyridyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(350 mg, 605 umol, 1.0 eq) in dioxane (3.0 mL) was added 4M HCl/dioxane(5.0 mL), the mixture was stirred at 20° C. for 0.5 hour. Aftercompletion, the reaction mixture was concentrated, then extracted withDCM (10.0 mL), the organic layer was washed with saturated NaHCO₃aqueous (2×10.0 mL), the organic layer was dried over Na₂SO₄, filteredand concentrated to give2-[(2S)-4-[7-(4-methoxy-3-pyridyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(260 mg, crude) as yellow oil which was used for the next step withoutfurther purification. LCMS [ESI, M+1]: 479.

Step C:2-[(2S)-4-[7-(4-methoxy-3-pyridyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a mixture of2-[(2S)-4-[7-(4-methoxy-3-pyridyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(260 mg, 543 umol, 1.0 eq) in DCM (5.0 mL) was added TEA (220 mg, 2.17mmol, 302 uL, 4.0 eq) and prop-2-enoyl chloride (63.9 mg, 706 umol, 57.6uL, 1.3 eq) at −60° C., the reaction mixture was stirred at −60° C. for0.5 hour. After completion, the reaction mixture was quenched with MeOH(2.0 mL), and concentrated. The residue was purified by columnchromatography (Base Al₂O₃, Petroleum ether:Ethyl acetate=3:1 to Ethylacetate/Methanol=20/1), then the crude product was concentrated andre-purified by prep-HPLC (column: Gemini 150*25 5 u; mobile phase:[water (0.04% NH₃H₂O)-ACN]; B %: 30%-54%, 10 min), the obtained productwas concentrated, and then under lyophilization Title compound2-[(2S)-4-[7-(4-methoxy-3-pyridyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 340, 83.6 mg, 155 umol, 29% yield, 98.8% purity) was obtainedas white solid. LCMS [ESI, M+1]: 533.

¹H NMR (400 MHz, Chloroform-d) δ 8.25 (d, J=5.2 Hz, 1H), 8.17 (s, 1H),6.82 (d, J=5.2 Hz, 1H), 6.38 (dd, J=1.2, 16.8 Hz, 1H), 6.44-6.33 (m,1H), 5.82 (br d, J=10.4 Hz, 1H), 5.21-4.52 (m, 1H), 4.37 (dd, J=4.8 Hz,10.4 Hz, 1H), 4.33-4.26 (m, 1H), 4.24-4.13 (m, 2H), 4.06 (br d, J=13.6Hz, 1H), 4.02-3.88 (m, 51H), 3.72-3.37 (m, 2H), 3.36-3.23 (m, 2H),3.16-3.02 (m, 2H), 2.98-2.88 (m, 1H), 2.87-2.72 (m, 3H), 2.70-2.60 (m,1H), 2.47 (s, 3H), 2.33-2.27 (m, 1H), 2.10-1.99 (m, 1H), 1.91-1.69 (m,3H).

Example 341

2-((S)-1-acryloyl-4-(2-(((S)-1-(2-hydroxyethyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[(2S)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-yl]methanol. To a mixture of [(2S)-pyrrolidin-2-yl]methanol(500 mg, 4.94 mmol, 481 uL, 1 eq) and2-bromoethoxy-tert-butyl-dimethyl-silane (1.30 g, 5.44 mmol, 1.1 eq) inMeCN (30 mL) was added K₂CO₃ (3.42 g, 24.7 mmol, 5 eq) in portion underN₂. The mixture was stirred at 50° C. for 12 hours. The reaction mixturewas filtered and the filtrate was concentrated under reduced pressure togive a residue. The residue was purified by column chromatography(Al₂O₃, Ethyl acetate/Methanol=100/1 to 5/1). Compound[(2S)-1-[2-[tert-butyl(dimenthyl)silyl]oxyethyl]pyrrolidin-2-yl]methanol(437 mg, 1.68 mmol, 34.0% yield) was obtained as a brown oil.

¹H NMR (400 MHz, chloroform-d) δ=3.71 (dd, J=5.2, 6.4 Hz, 2H), 3.63-3.58(m, 1H), 3.37 (dd, J=3.2, 10.8 Hz, 1H), 3.21 (td, J=4.8, 10.0 Hz, 1H),2.90 (td, J==6.4, 12.8 Hz, 1H), 2.74-2.67 (m, 1H), 2.52 (td, J=5.2, 10.4Hz, 1H), 2.41-2.31 (m, 1H), 1.97-1.80 (m, 1H), 1.79-1.55 (m, 3H),0.92-0.87 (m, 9H), 0.11-0.00 (m, 6H).

Step A: benzyl(2)-4-[2-[[(2S)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.To a mixture of [(2S)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-yl]methanol (447 mg, 1.72 mmol, 2 eq) in toluene (35 mL)was added t-BuONa (248 mg, 2.58 mmol, 3 eq) in portion, then to thesolution was added benzyl(2S)-2-(cyanomethyl)-4-[2-methylsulfinyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(Intermediate 66, 500 mg, 861 umol, 1 eq) at 0° C. The mixture waswarmed to 25° C. and stirred for 1 hour. The reaction mixture wasdiluted with ethyl acetate 20 mL and adjusted PH to 8-9 with 2M HCl at0° C., then extracted with ethyl acetate (20 mL×3). The combined organiclayers were washed with water (15 mL 1), dried over sodium sulfate,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=100/1 to 1/2). Compound benzyl(2S)-4-[2-[[(2S)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(400 mg, 494 umol, 57.4% yield, 95.8% purity) was obtained as acolorless oil. LCMS [ESI, M+1]: 776.

Step B: 2-[(2S)-4-[2-[[(2S)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of benzyl (2S)-4-[2-[[(2S)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(380 mg, 490 umol, 1 eq) in MeOH (30 mL) was added Pd/C (230 mg, 490umol, 10% purity, 1.00 eq) and NH₃·MeOH (25 mL). The suspension wasdegassed under vacuum and purged with H₂ three times. The mixture wasstirred under H₂ (15 psi) at 25° C. for 1 hour. The reaction mixture wasfiltered and concentrated under reduced pressure to give a residue.Compound 2-[(2S)-4-[2-[[(2S)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(314 mg, 489 umol, 99.9% yield) was obtained as a yellow oil and useddirectly into the next step without further purification. LCM S [ESI,M+1]: 642.

Step C: 2-[(2S)-4-[2-[[(2S)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a mixture of 2-[(2S)-4-[2-[[(2S)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(314 mg, 489 umol, 1 eq) in DCM (15 mL) was added TEA (148 mg, 1.47mmol, 204 uL, 3 eq) and prop-2-enoyl chloride (57.6 mg, 636 umol, 51.9uL, 1.3 eq) in portion at −40° C. under N₂. The mixture was stirred at−40° C. for 30 min. The reaction mixture was quenched by addingsaturated NaHCO₃ solution 3 mL at −40° C., and then extracted with DCM(20 mL×3). The combined organic layers were washed with brine (15 mL×1),dried over sodium sulfate, filtered and concentrated under reducedpressure to give a residue. The residue was purified by columnchromatography (Al₂O₃, Petroleum ether/Ethyl acetate=100/1 to 1/3).Compound 2-[(2S)-4-[2-[[(2S)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(210 mg, 300 umol, 61.4% yield, 99.5% purity) was obtained as acolorless oil. LCMS [ESI, M+1]: 696.

Step D: 2-[(2S)-4-[2-[[(2S)-1-(2-hydroxyethyl)pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a mixture of 2-[(2S)-4-[2-[[(2S)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(205 mg, 295 umol, 1 eq) in THF (3 mL) was added KF (171 mg, 2.95 mmol,69.0 uL, 10 eq) and 18-crown-6 (779 mg, 2.95 mmol, 10 eq) in portion.The mixture was stirred at 40° C. for 2 hours. The reaction mixture wasfiltered and concentrated under reduced pressure to give a residue. Theresidue was purified by prep-HPLC (column: Phenomenex Gemini 150*25mm*10 um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %:45%-75%, 12 min). Title compound 2-[(2S)-4-[2-[[(2S)-1-(2-hydroxyethyl)pyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 341, 43.4 mg, 71.6 umol, 24.3% yield, 95.9% purity) wasobtained as a white solid. LCMS [ESI, M+1]: 582.

SFC: “OJ-3S_3_5_40_3 ML Column: Chiralcel OJ-3 100×4.6 mm I.D., 3 umMobile phase: methanol (0.05% DEA) in CO₂ from 5% to 40% Flow rate: 3mL/min Wavelength. 220 nm”.

¹H NMR (400 MHz, chloroform-d) δ=8.24-8.18 (m, 1H), 7.89-7.83 (m, 1H),7.61 (d, J=8.4 Hz, 1H), 7.54-7.47 (m, 2H), 7.44 (t, J=7.2 Hz, 1H), 7.15(d, J=6.8 Hz, 1H), 6.60 (br s, 1H), 6.40 (dd, J=1.6, 16.8 Hz, 1H), 5.84(br d, J=10.4 Hz, 1H), 5.11 (br s, 1H), 4.36-4.22 (m, 3H), 4.16 (dd,J=6.8, 10.4 Hz, 2H), 4.01 (br d, J=11.6 Hz, 1H), 3.72-3.55 (m, 3H),3.53-3.26 (m, 3H), 3.24-2.68 (m, 10H), 2.62 (td, J=4.0, 12.5 Hz, 1H),2.39-2.28 (m, 1H), 2.07-1.96 (m, 1H), 1.90-1.75 (m, 3H).

Example 342

2-[(2S)-1-[(E)-4-(dimethylamino)but-2-enoyl]-4-[7-[3-fluoro-2-(trifluoromethyl)phenyl]-2-[[(2S,4R)-4-hydroxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

Step A: benzyl(2S)-2-(cyanomethyl)-4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate.To a solution tert-butyl4-[(3S)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(3.00 g, 5.57 mmol, 1.00 eq) in dioxane (30.0 mL) was added HCl/dioxane(4.00 M, 30.0 mL, 21.6 eq) at 0° C. After stirred at 25° C. for 1 hour,the mixture was concentrated under vacuum. The residue was diluted withwater (4.00 mL), adjusted pH>8 by saturated sodium bicarbonate (10.0 mL)and extracted with ethyl acetate (3×30.0 mL). The extracts were driedover Na₂SO₄, filtered and concentrated under vacuum. The residue waspurified by column chromatography (Al₂O₃, methanol/ethyl acetate=10/1)to give benzyl(2S)-2-(cyanomethyl)-4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(2.10 g, 4.02 mmol, 72% yield) as a yellow solid. LCMS [ESI, M+1]: 439.

¹H NMR (400 MHz, chloroform-d) δ=7.46-7.30 (m, 5H), 5.25-5.14 (m, 2H),4.66 (br s, 1H), 4.14-4.05 (m, 1H), 4.04-3.90 (m, 3H), 3.84 (br d,J=12.4 Hz, 1H), 3.26 (br d, J=11.6 Hz, 2H), 3.12 (td, J=5.2, 12.4 Hz,1H), 3.05-2.91 (m, 2H), 2.79 (br s, 1H), 2.74-2.56 (m, 3H), 2.49 (s,3H).

Step B: benzyl(2S)-2-(cyanomethyl)-4-[7-[3-fluoro-2-(trifluoromethyl)phenyl]-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.A mixture of benzyl(2S)-2-(cyanomethyl)-4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(2.00 g, 4.56 mmol, 1.00 eq),1-bromo-3-fluoro-2-(trifluoromethyl)benzene (1.66 g, 6.84 mmol, 1.50eq), Pd₂(dba)₃ (418 mg, 456 umol, 0.10 eq), RuPhos (426 mg, 912 umol,0.20 eq) and Cs₂CO₃ (2.97 g, 9.12 mmol, 2.00 eq) in toluene (30.0 mL)was stirred at 90° C. for 5 hours. The mixture was diluted with water(20.0 mL), extracted with ethyl acetate (3×30.0 mL). The organic layerswere washed with brine (1×40.0 mL), dried over Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by reversed phaseflash [water (TFA, 0.10%)/acetonitrile]. The desired fractions werecollected and adjusted pH>7 by saturated sodium bicarbonate (5.00 mL),extracted with ethyl acetate (3×30.0 mL), dried over Na₂SO₄, filteredand concentrated under vacuum to give benzyl(2S)-2-(cyanomethyl)-4-[7-[3-fluoro-2-(trifluoromethyl)phenyl]-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(2.00 g, 2.90 mmol, 64% yield) as a yellow solid. LCMS [ESI, M+1]: 601.

¹H NMR (400 MHz, chloroform-d) δ=7.53-7.44 (m, 1H), 7.43-7.29 (m, 5H),7.07 (d, J=8.0 Hz, 1H), 7.00-6.91 (m, 1H), 5.26-5.13 (m, 2H), 4.69 (brs, 1H), 4.16-4.10 (m, 3H), 4.04 (br d, J=13.2 Hz, 1H), 3.87 (br d,J=12.4 Hz, 1H), 3.39-3.22 (m, 3H), 3.19-3.09 (m, 1H), 3.04 (dt, J=3.6,12.4 Hz, 1H), 2.83 (br s, 2H), 2.76-2.67 (m, 2H), 2.51 (s, 3H).

Step C: benzyl(2S)-2-(cyanomethyl)-4-[7-[3-fluoro-2-(trifluoromethyl)phenyl]-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[7-[3-fluoro-2-(trifluoromethyl)phenyl]-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1.90 g, 3.16 mmol, 1.00 eq) in ethyl acetate (50.0 mL) was added m-CPBA(610 mg, 3.01 mmol, 85% purity, 0.95 eq) at 0° C. After stirred at 0° C.for 0.5 h, the mixture was diluted with water (30.0 mL), adjusted pH>7by saturated sodium bicarbonate (10.0 mL) and extracted with ethylacetate (3×20.0 mL). The organic layers were washed with brine (1×40.0mL), dried over Na₂SO₄, filtered and concentrated under vacuum. Theresidue was purified by column chromatography (SiO₂, petroleumether/ethyl acetate=1/3) to give benzyl(2S)-2-(cyanomethyl)-4-[7-[3-fluoro-2-(trifluoromethyl)phenyl]-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1.20 g, 1.73 mmol, 55% yield) as a yellow solid. LCMS [ESI, M+1]: 617.

¹H NMR (400 MHz, chloroform-d) δ=7.55-7.47 (m, 1H), 7.44-7.33 (m, 5H),7.08 (d, J=8.0 Hz, 1H), 7.03-6.94 (m, 1H), 5.20 (s, 2H), 4.68 (br s,1H), 4.31-4.09 (m, 4H), 4.02 (br d, J=12.0 Hz, 1H), 3.46 (br d, J=13.2Hz, 1H), 3.40-3.09 (m, 4H), 2.90 (br d, J=2.8 Hz, 6H), 2.74-2.64 (m,1H).

Step D: benzyl(2S)-4-[2-[[(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-[3-fluoro-2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.To a solution of[(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methanol(145 mg, 392 umol, 1.10 eq) in THF (5.00 mL) was added t-BuONa (68.6 mg,714 umol, 2.00 eq) at 0° C. Then benzyl(2S)-2-(cyanomethyl)-4-[7-[3-fluoro-2-(trifluoromethyl)phenyl]-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.22 g, 357 umol, 1.00 eq) was added into the mixture. After stirred at0° C. for 0.5 h, the mixture was diluted with ethyl acetate (10.0 m L)and water (10.0 mL), and then extracted with ethyl acetate (3×10.0 mL).The extracts were washed with brine (1×20.0 mL), dried over Na₂SO₄,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography (Al₂O₃, petroleum ether/ethyl acetate=1/3) to givebenzyl(2S)-4-[2-[[(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-[3-fluoro-2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(0.18 g, 185 umol, 52% yield) as a yellow solid. LCMS [ESI, M/2+1]: 462.

Step E:2-[(2S)-4-[2-[[(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-[3-fluoro-2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.NH₃ was bubbled in methanol (30.0 mL) at −78° C. for 15 minutes. Benzyl(2S)-4-[2-[[(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-[3-fluoro-2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(0.18 g, 195 umol, 1.00 eq) and Pd/C (0.10 g, 10% purity) was added intothe mixture. After stirred at 40° C. for 1 hour under H₂ at 15 psi, thecatalyst was filtered and concentrated under vacuum to give2-[(2S)-4-[2-[[(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-[3-fluoro-2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(0.13 g, crude) as a yellow solid. LCMS [ESI, M/2+1]: 395.

Step F:2-[(2S)-4-[2-[[(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-[3-fluoro-2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-(dimethylamino)but-2-enoyl]piperazin-2-yl]acetonitrile.A mixture of (E)-4-bromobut-2-enoic acid (0.50 g, 3.03 mmol, 1.00 eq)and oxalyl dichloride (3.85 g, 30.31 mmol, 2.65 mL, 10.0 eq) indichloromethane (5 mL) was stirred at 0° C. for 0.5 h and 40° C. for 2hours. The mixture was concentrated under vacuum. The above residue(93.0 mg, crude) was added into the mixture of2-[(2S)-4-[2-[[(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-[3-fluoro-2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(80.0 mg, crude) and Py (80.3 mg, 1.02 mmol, 82.0 uL) in dichloromethane(0.50 mL) at 0′° C. After stirred at 0° C. for 0.5 h,N-methylmethanamine (69.4 mg, 508 umol, 77.9 uL) was added and themixture was stirred at 20° C. for 1 hour. Then the mixture wasconcentrated under vacuum. The residue was purified by reversed phaseflash [water (TFA, 0.10%)]. The desired fractions were adjusted pH>7 bysaturated sodium bicarbonate (1×5.00 mL) and extracted with ethylacetate (3×10.0 mL). The extracts were washed with brine (1×10.0 mL),dried over Na₂SO₄, filtered and concentrated under vacuum to give2-[(2S)-4-[2-[[(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-[3-fluoro-2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-(dimethylamino)but-2-enoyl]piperazin-2-yl]acetonitrile(0.06 g, 48.05 umol, two steps 65% yield) was obtained as a yellow oil.LCMS [ESI, M+1]: 899.

Step G:2-[(2S)-1-[(E)-4-(dimethylamino)but-2-enoyl]-4-[7-[3-fluoro-2-(trifluoromethyl)phenyl]-2-[[(2S,4R)-4-hydroxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.A mixture of2-[(2S)-4-[2-[[(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-[3-fluoro-2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-(dimethylamino)but-2-enoyl]piperazin-2-yl]acetonitrile(0.06 g, 66.7 umol, 1.00 eq), KF (38.8 mg, 667 umol, 15.6 uL, 10.0 eq)and 18-crown-6 (176 mg, 667 umol, 10.0 eq) in THF (0.10 mL) was stirredat 40° C. for 12 hours. The mixture was concentrated under vacuum. Theresidue was purified by reversed phase flash [water (TFA,0.10%/acetonitrile)] and prep-HPLC column: Gemini 150*25 5 u; mobilephase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 30%-60%, 12 min.The desired fractions were collected and lyophilized to give titlecompound2-[(2S)-1-[(E)-4-(dimethylamino)but-2-enoyl]-4-[7-[3-fluoro-2-(trifluoromethyl)phenyl]-2-[[(2S,4R)-4-hydroxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(EXAMPLE 342, 4.60 mg, 6.91 umol, 10% yield, 99.2% purity) as a whitesolid. LCMS [ESI, M+1]:661.

¹H NMR (400 MHz, chloroform-d) δ=7.52-7.44 (m, 1H), 7.07 (d, J=8.4 Hz,1H), 7.00-6.90 (m, 2H), 6.46 (br d, J=15.2 Hz, 1H), 5.07 (br s, 1H),4.50-4.42 (m, 1H), 4.36 (dd, J=4.8, 10.8 Hz, 1H), 4.22 (dd, J=5.6, 10.8Hz, 1H), 4.16-4.06 (m, 3H), 3.96 (br d, J=11.6 Hz, 2H), 3.60 (br s, 1H),3.43 (dd, J=6.0, 10.0 Hz, 1H), 3.39-3.23 (m, 2H), 3.20-3.05 (m, 4H),3.05-2.79 (m, 4H), 2.78-2.62 (m, 2H), 2.48 (s, 3H), 2.35-2.26 (m, 71f),2.12-1.92 (m, 2H).

(S)-7-(2,3-dimethylphenyl)-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(4-(vinylsulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

Step A:7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine.To a solution of tert-butyl4-[7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(350 mg, 652 umol, 1.0 eq) in dioxane (3.0 mL) was added 4M HCl/dioxane(5.0 mL), the mixture was stirred at 20° C. for 0.5 hour. Aftercompletion, the reaction mixture was concentrated, then added DCM (10.0mL), the organic layer was washed with saturated NaHCO₃ aqueous (2×10.0mL), the organic layer was dried over Na₂SO₄, filtered and concentratedto give7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(280 mg, crude) as yellow oil which was used for the next step withoutfurther purification. LCMS [ESI, M+1]: 437.

Step B:7-(2,3-dimethylphenyl)-2-[[(2S)-methylpyrrolidin-2-yl]methoxy]-4-(4-vinylsulfonylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine.To a mixture of7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(280 mg, 641 umol, 1.0 eq) in DCM (5.0 mL) was added TEA (195 mg 1.92mmol, 268 uL, 3.0 eq) and ethenesulfonyl chloride (122 mg, 962 umol, 1.5eq) at −60° C., the reaction mixture was stirred at −60° C. for 0.5hour. After completion, the reaction mixture was quenched with MeOH (1.0mL), and concentrated. The residue was purified by column chromatography(Base Al₂O₃, Petroleum ether:Ethyl acetate=3:1-Ethylacetate/Methanol=20/1), then the crude product was concentrated andrepurified by prep-HPLC (column: Phenomenex Gemini 150*25 mm*10 um;mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 62%-92%,12 min), the obtained product was concentrated, and then underlyophilization. Title compound7-(2,3-dimethylphenyl)-2-[[(2S)-methylpyrrolidin-2-yl]methoxy]-4-(4-vinylsulfonylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(EXAMPLE 343, 98.2 mg, 185 umol, 29% yield, 99.3% purity) was obtainedas white solid. LCMS [ESI, M+1]: 527.

¹H NMR (400 MHz, chloroform-d) δ 7.12 (t, J=7.6 Hz, 1H), 7.00-6.94 (m,2H), 6.47 (dd, J=10.0 Hz, 16.8 Hz, 1H), 6.30 (d, J=16.8 Hz, 1H), 6.11(d, J=10.0 Hz, 1H), 4.39 (dd, J=4.8, 10.4 Hz, 1H), 4.15 (dd, J=6.8, 10.4Hz, 1H), 4.03 (s, 2H), 3.62 (t, J=4.6 Hz, 4H), 3.30 (t, J=4.6 Hz, 4H),3.19-3.05 (m, 3H), 2.80-2.62 (m, 3H), 2.49 (s, 3H), 2.32-2.25 (m, 7H),2.13-2.00 (m, 1H), 1.92-1.72 (m, 3H).

Example 344

2-[(2S)-4-[7-(3-hydroxy-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: benzyl(2S)-4-[7-(3-benzyloxy-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.To a solution of [(2R)-1-methylpyrrolidin-2-yl]methanol (101 mg, 874umol, 1.2 eq) in toluene (15 mL) was added t-BuONa (140 mg, 1.46 mmol, 2eq) at 0° C. under 10 minutes. Then to the mixture was added a solutionof benzyl(2S)-4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(Intermediate 64, 500 mg, 728 umol, 1 eq) in toluene (10 mL) dropwise at0° C. After stirred at 0° C. for 0.5 h, the reaction mixture was dilutedwith H₂O (1×7 mL) and Ethyl acetate (1×25 mL). The organic phase wasseparated, washed with brine (1×20 mL), dried over sodium sulfate,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by column chromatography (Al₂O₃; Petroleumether/Ethyl acetate=10/1 to 0/1). Compound benzyl(2S)-4-[7-(3-benzyloxy-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(390 mg, 489 umol, 67% yield, 92.6% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 738.

¹H NMR (400 MHz, chloroform-d) δ=8.09 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.0Hz, 1H), 7.50 (d, J=7.2 Hz, 2H), 7.46-7.34 (m, 10H), 7.00 (d, J=20 Hz,1H), 6.89 (d, J=2.4 Hz, 1H), 5.24-5.15 (m, 4H), 4.70 (br s, 1H), 4.39(dd, J=4.8, 10.7 Hz, 1H), 4.33-4.22 (m, 2H), 4.20-4.11 (m, 3H), 3.93 (brd, J=12.0 Hz, 1H), 3.56-3.19 (m, 4H), 3.14-2.61 (m, 7H), 2.48 (s, 3H),2.34-2.23 (m, 1H), 2.11-2.06 (m, 1H), 1.84-1.69 (m, 3H).

Step B:2-[(2S)-4-[7-(3-hydroxy-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.NH₃ was bubbled into MeOH (100 mL) at −60° C. for 20 minutes. To asolution of benzyl(2S)-4-[7-(3-benzyloxy-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(360 mg, 488 umol, 1 eq) in MeOH (25 mL) was added Pd/C (300 mg, 10%purity) and the above solution (NH₃·MeOH, 25 mL) under N₂. Thesuspension was degassed under vacuum and purged with H₂ several times.The mixture was stirred under H₂ (15 psi) at 25° C. for 1 hour. Thecatalyst was filtered off and concentrated under vacuum. Compound2-[(2S)-4-[7-(3-hydroxy-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(230 mg, crude) was obtained as a yellow oil. LCMS [ESI, M+1]: 514.

Step C:2-[(2S)-4-[7-(3-hydroxy-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a mixture of2-[(2S)-4-[7-(3-hydroxy-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(230 mg, crude) and TEA (453 mg, 4.48 mmol, 623 uL) in DCM (8 mL) wasadded prop-2-enoyl chloride (40.5 mg, 448 umol, 36.5 uL) in portion at−40° C. The mixture was stirred at −40° C. for 30 min. The reactionmixture was quenched with NaHCO₃ saturated solution (2 mL) at 0° C., andthen extracted with CH₂Cl₂ (2×30 mL). The combined organic layers werewashed with brine (1×30 mL), dried over sodium sulfate, filtered andconcentrated under vacuum to give a residue. The residue was purified bycolumn chromatography (Al₂O₃; Ethyl acetate/Methanol=20/1 to 3/1). Theresidue was purified by prep-HPLC (column: Phenomenex Gemini 150*25mm*10 um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %:38%-68%, 12 min). Title compound2-[(2S)-4-[7-(3-hydroxy-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 344, 25.6 mg, 44.8 umol, two steps 9.2% yield, 99.5% purity)was obtained as a yellow solid. LCMS [ESI, M+1]: 568.

SFC condition: “AS-3_MeOH (DEA)_5_40_3 mL-35T Column: Chiralpak AS-350×4.6 mm I.D., 3 um Mobile phase: methanol (0.05% DEA) in CO₂ from 5%to 40% Flow rate: 3 mL/min Wavelength: 220 nm”.

¹H NMR (400 MHz, acetic) δ=8.08 (d, J=8.4 Hz, 1H), 7.66 (d, J=8.0 Hz,1H), 7.39 (t, J=7.6 Hz, 1H), 7.29 (t, J=7.2 Hz, 1H), 6.96 (s, 1H),6.90-6.68 (m, 2H), 6.38 (br d, J=17.6 Hz, 1H), 5.87 (br d, J=10.8 Hz,1H), 5.17 (br s, 1H), 4.82 (br s, 2H), 4.59 (br s, 1H), 4.45-4.25 (m,3H), 4.21-3.61 (m, 4H), 3.60-3.19 (m, 5H), 3.17-2.83 (m, 7H), 2.45-2.31(m, 1H), 2.23-2.10 (m, 3H).

Example 345

2-[(2S)-4-[7-(3-methyl-4-pyridyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A:tert-butyl(2S)-2-(cyanomethyl)-4-[7-(3-methyl-4-pyridyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.A mixture of tert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(700 mg, 1.48 mmol, 1.0 eq), 4-chloro-3-methyl-pyridine (379 mg, 2.97mmol, 2.0 eq), Pd₂(dba)₃ (204 mgs, 223 umol, 0.15 eq), RuPhos (139 mg,297 umol, 0.2 eq) and Cs₂CO₃ (1.45 g, 4.45 mmol, 3.0 eq) in toluene(10.0 mL) was degassed and purged with N₂ for 3 times, and then themixture was stirred at 90° C. for 12 hrs under N₂ atmosphere. Theorganic solvent was removed under vacuum, and washed with water (15.0mL). The aqueous phase was extracted with ethyl acetate (3×25.0 mL).Combine extracts were washed with brine (60.0 mL), dried with Na₂SO₄ thesolvent was then removed under vacuum. The residue was purified byreversed phase flash HPLC [C18, 0.1% FA in water, 0-45% MeCN]. Theobtained product was adjusted with saturated NaHCO₃ aqueous to pH˜8,then concentrated, the aqueous was extracted with ethyl acetate (3×50.0mL), the combined organic layer was dried over Na₂SO₄, filtered andconcentrated. Compoundtert-butyl(2S)-2-(cyanomethyl)-4-[7-(3-methyl-4-pyridyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(270 mg, 475 umol, 32% yield, 99.0% purity) was obtained as yellowsolid. LCMS [ESI, M+1]: 563.

Step B:2-[(2S)-4-[7-(3-methyl-4-pyridyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-2-(cyanomethyl)-4-[7-(3-methyl-4-pyridyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 355 umol, 1.0 eq) in dioxane (3.0 mL) was added HCl· dioxane (4M, 3.0 mL, 33.8 eq). The mixture was stirred at 25° C. for 30 min underN₂ atmosphere. The organic solvent was removed under vacuum. Theobtained product was adjusted with saturated NaHCO₃ aqueous to pH˜8,then concentrated, the aqueous was extracted with ethyl acetate (3×15.0mL), the combined organic layer was dried over Na₂SO₄, filtered andconcentrated. The crude product2-[(2S)-4-[7-(3-methyl-4-pyridyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(125 mg, crude) was obtained as a yellow solid and used into the nextstep without further purification. LCMS [ESI, M+1]: 463.

Step C:2-[(2S)-4-[7-(3-methyl-4-pyridyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(3-methyl-4-pyridyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(125 mg, crude) in DCM (3.0 mL) was added TEA (137 mg, 1.35 mmol, 188uL) and prop-2-enoyl chloride (36.7 mg, 405 umol, 33.1 uL) at −60° C.The mixture was stirred at −60° C. for 30 min. The reaction was quenchedwith methanol (10.0 mL) and the mixture was removed under vacuum. Theresidue was purified by prep-HPLC (column: Phenomenex Gemini 150*25mm*10 um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %:32%-62%, 12 min) and lyophilization. Title compound2-[(2S)-4-[7-(3-methyl-4-pyridyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 345, 25.3 mg, 48.4 umol, 18% yield, 99% purity) was obtained asa white solid LCMS [ESI, M+1]: 517.

¹H NMR (400 MHz, CHLOROFORM-d) δ=8.33-8.29 (m, 2H), 6.83 (d, J=5.6 Hz,1H), 6.65-6.50 (m, 1H), 6.38 (dd, J=1.6 Hz, J=16.8 Hz, 1H), 5.82 (d,J=10.8 Hz 1H), 5.41 (br s, 1H), 4.36 (dd, J=4.8 Hz, J=10.4 Hz, 1H),4.20-4.06 (m, 4H), 4.97 (br d, J=11.6 Hz 2H), 3.68-3.45 (m, 1H),3.40-3.31 (m, 2H), 3.26-3.15 (m, 1H), 3.15-3.03 (m, 2H), 2.97-2.60 (m,5H), 2.31 (s, 3H), 2.29-2.21 (m, 3H), 2.15-2.10 (m, 1H), 2.09-2.00 (m,1H), 1.88-1.70 (m, 3H).

Example 346

2-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-[2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step 1: To a solution of (E)-4-bromobut-2-enoic acid (1.0 g, 6.06 mmol,1.0 eq) in DCM (5.0 mL) was added (COCl)₂ (8.70 g, 68.5 mmol, 6 mL, 11.3eq). The mixture was stirred at 60° C. for 16 hrs under N₂ atmosphere.The organic solvent was removed under vacuum. The crude product(E)-4-bromobut-2-enoyl chloride (1.3 g, crude) was obtained as a yellowliquid and used into the next step without further purification.

Step A: tert-butyl(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.To a solution of tert-butyl(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(1.30 g, 2.17 mmol, 1.0 eq) and [(2S)-1-methylpyrrolidin-2-yl]methanol(500 mg, 4.34 mmol, 515 uL, 2.0 eq) in toluene (20.0 mL) was addedt-BuONa (417 mg, 4.34 mmol, 2.0 eq). The mixture was stirred at 0° C.for 10 min. The reaction mixture was quenched by adding saturated brine(30 mL) at 20° C., and extracted with EA (3×30.0 mL). The combinedorganic layers were washed with saturated brine (30.0 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=3/1 to EA/MeOH=10/1). The producttert-butyl(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(1.10 g, 1.62 mmol, 75% yield, 96% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 650.

Step B:2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(200 mg, 308 umol, 1.0 eq) in dioxane (2.0 mL) was added HCl/dioxane (4M. 2.0 mL, 26.0 eq). The mixture was stirred at 25° C. for 30 min underN₂ atmosphere. The organic solvent was removed under vacuum. Theobtained product was adjusted with saturated NaHCO₃ aqueous to pH˜8,then concentrated, the aqueous was extracted with ethyl acetate (3×20.0mL), the combined organic layer was dried over Na₂SO₄, filtered andconcentrated. The crude product2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(130 mg, crude) was obtained as a yellow solid and used into the nextstep without further purification. LCMS [ESI, M+1]: 551.

Step C:2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-morpholinobut-2-enoyl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(100 mg, 1812 umol, 1.0 eq) and PYRIDINE (115 mg, 1.45 mmol, 117 uL, 8.0eq) in DCM (3.0 mL) was added (E)-4-bromobut-2-enoyl chloride (133 mg,727 umol, 4.0 eq). The mixture was stirred at 0° C. for 0.5 hr. Afterthe starting material was consumed, morpholine (79.2 mg, 909 umol, 80.0uL, 5.0 eq) was added to the above mixture and stirred at 0° C. for 3.5hrs. The organic solvent was removed under vacuum. The obtained productwas adjusted with saturated NaHCO₃ aqueous to pH˜8, then concentrated,the aqueous was extracted with ethyl acetate (3×15.0 mL), the combinedorganic layer was dried over Na₂SO₄, filtered and concentrated. Titlecompound2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-morpholinobut-2-enoyl]piperazin-2-yl]acetonitrile(EXAMPLE 346, 21.7 mg, 30.6 umol, 16.9% yield, 99% purity) was obtainedas a yellow solid. LCMS [ESI, M+1]: 703.

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.40 (t, J=8.0 Hz, J=8.0 Hz 1H), 7.28(s, 1H), 7.19 (d, J=8.0 Hz, 1H), 7.00-6.93 (m, 1H), 6.59 (br s, 1H),6.57-6.40 (m, 1H), 5.18-5.03 (m, 1H), 4.38 (dd, J=4.8 Hz, J=10.4 Hz,1H), 4.16 (dd, J=6.8 Hz, J=10.4 Hz, 1H), 4.14-4.04 (m, 3H), 4.04-3.88(m, 2H), 3.74 (t, J=4.4 Hz, J=4.8 Hz, 4H), 3.52 (br s, 1H), 3.41-3.23(m, 2H), 3.18 (d, J=5.6 Hz, 3H), 3.12-3.08 (m, 2H), 2.95-2.85 (m, 2H),2.30-2.15 (m, 3H), 2.55-2.45 (m, 7H), 2.34-2.24 (m, 1H), 2.13-2.00 (m,1H), 1.90-1.75 (m, 3H).

Example 347

2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-pyrrolidin-1-ylbut-2-enoyl]piperazin-2-yl]acetonitrile

Insert: (E)-4-bromobut-2-enoyl chloride. A solution of(E)-4-bromobut-2-enoic acid (1.00 g, 6.06 mmol, 1.00 eq) in (COCl)₂(14.5 g, 114 mmol, 10.0 mL, 18.9 eq) and DCM (10.0 mL) was stirred at70° C. for 2 hours. After completion, the mixture was concentrated undervacuum. The product (E)-4-bromobut-2-enoyl chloride (1.00 g crude) wasobtained as yellow oil. The crude compound was used directly to the nextstep without further purification.

Step A:2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(700 mg, 1.08 mmol, 1.0 eq) in dioxane (5.0 mL) was added HCl·dioxane (4M, 7.0 mL, 26.0 eq) at 0° C. The mixture was stirred at 0° C. for 2hours. After completion, the mixture was concentrated and adjusts withsaturated NaHCO₃ aqueous to pH˜7, then extracted with EA (10.0 mL×3).The organic layer was dried over Na₂SO₄, filtered and concentrated. Theproduct2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(400 mg, 669 umol, 62% yield, 92% purity) was obtained as yellow oilLCMS [ESI, M+1]: 550.

Step B:2-[(2S)-1-[(E)-4-bromobut-2-enoyl]-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(200 mg, 364 umol, 1.00 eq) and Pyridine (230 mg, 2.91 mmol, 235 uL, 8.0eq) in DCM (2.0 mL) was added (E)-4-bromobut-2-enoyl chloride (267 mg,1.45 mmol, 4.0 eq). The mixture was stirred at 0° C. for 0.5 hour. Aftercompletion, the mixture was added water (10.0 mL) and extracted with DCM(10.0 mL×2). The organic layer was dried over Na₂SO₄, filtered andconcentrated. The product2-[(2S)-1-[(E)-4-bromobut-2-enoyl]-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(300 mg, crude) was obtained as brown oil.

Step C:2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-pyrrolidin-1-ylbut-2-enoyl]piperazin-2-yl]acetonitrile.To a solution of pyrrolidine (306 mg, 4.30 mmol, 359 uL, 10.0 eq), K₂CO₃(297 mg, 2.15 mmol, 5.0 eq) and K1 (21.4 mg, 129 umol, 0.30 eq) in THF(2.0 mL) was added2-[(2S)-1-[(E)-4-bromobut-2-enoyl]-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(300 mg, 430 umol, 1.0 eq) in portions at 0° C. The mixture was stirredat 0° C. for 0.5 hour. After completion, water (10.0 mL) was added tothe mixture and extracted with DCM (10.0 mL×3). The organic layer wasdried over Na₂SO₄, filtered and concentrated. The obtained product waspurified by prep-HPLC (column: Phenomenex Gemini C18 250*50 mm*10 um;mobile phase: [water(10 mM NH₄HCO₃)-ACN]; B %: 70%-100%, 3 min) to givetitle compound2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-pyrrolidin-1-ylbut-2-enoyl]piperazin-2-yl]acetonitrile(EXAMPLE 347, 17.1 mg, 24.5 umol, two steps 7% yield, 99% purity) asyellow oil. LCMS [ESI, M+1]: 687.

¹H NMR (400 MHz, Chloroform-d) δ 7.41 (t, J=8.0 Hz, 1H), 7.28 (d, J=8.0Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.06-6.95 (m, 1H), 6.47 (br d, J=14.0Hz, 1H), 5.20-4.60 (m, 1H), 4.39 (dd, J=5.2, 10.8 Hz, 1H), 4.22-4.07 (m,4H), 3.97 (br d, J=12.0 Hz, 2H), 3.42-3.23 (m, 3H), 3.21-3.04 (m, 3H),2.96-2.86 (m, 2H), 2.79-2.64 (m, 5H), 2.62-2.54 (m, 4H), 2.49 (s, 3H),2.35-2.25 (m, 1H), 2.13-2.01 (m, 1H), 1.83-1.70 (m, 7H).

Example 348

2-[(2S)-4-[7-(3-hydroxy-1-naphthyl)-2-[(1R)-1-[(2R)-1-methylpyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Insert: tert-Butyl(2R)-2-[(1R)-1-hydroxyethyl]pyrrolidine-1-carboxylate. A mixture ofBH₃·Me₂S (10 M in DMS, 610 uL, 1.3 eq) and(3aS)-1-methyl-3,3-diphenyl-3a,4,5,6-tetrahydropyrrolo[1,2-c][1,3,2]oxazaborole(1 M in toluene, 938 uL, 0.2 eq) in THF (10 mL) was stirred at 25° C.for 1 hour. Then a solution of tert-butyl(2R)-2-acetylpyrrolidine-1-carboxylate (1.00 g, 4.69 mmol, 1 eq) in THF(10 mL) was added and the mixture stirred at 25° C. for 1 hour. Themixture was quenched with MeOH (4 mL), concentrated under vacuum. Theresidue was purified by column chromatography (SiO₂, PE/EtOAC=50/1 to5/1). tert-Butyl (2R)-2-[(1R)-1-hydroxyethyl]pyrrolidine-1-carboxylate(690 mg, 3.21 mmol, 68% yield) was obtained as a white solid.

¹H NMR (400 MHz, chloroform-d) δ=5.19 (br s, 1H), 3.79-3.59 (m, 2H),3.49 (br s, 1H), 3.35-3.18 (m, 1H), 2.04-1.90 (m, 1H), 1.88-1.68 (m,3H), 1.47 (d, J=0.8 Hz, 9H), 1.20-1.11 (m, 3H).

Step A: benzyl(2S)-4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-1-[(2R)-1-tert-butoxycarbonylpyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.To a solution of tert-butyl(2R)-2-[(1R)-1-hydroxyethyl]pyrrolidine-1-carboxylate (263 mg, 1.22mmol, 1.2 eq) in toluene (15 mL) was added t-BuONa (196 mg, 2.04 mmol, 2eq) at 0° C. for 10 minutes. To the mixture was added benzyl(2S)-4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(700 mg, 1.02 mmol, 1 eq) in toluene (15 mL) dropwise at 0° C. Afterstirred at 0° C. for 0.5 h, the reaction mixture was added H₂O (1×7 mL)and ethyl acetate (1×35 mL). The organic phase was separated, washedwith brine (1×20 mL), dried over sodium sulfate, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by reversed phase flash [water (0.1% FA)/acetonitrile]. Thedesired fractions were collected and neutralized to pH=7 with saturatedNaHCO₃ solution and extracted with ethyl acetate (1×100 mL). Theseparated organic layer was dried over sodium sulfate, filtered andconcentrated under vacuum. Compound benzyl(2S)-4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-1-[(2R)-1-tert-butoxycarbonylpyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(470 mg, 536 umol, 53% yield, 95.6% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 838.

¹H NMR (400 MHz, chloroform-d) δ=8.09 (d, J=8.4 Hz, 1H), 7.73 (d, J=8.0Hz, 1H), 7.53-7.48 (m, 2H), 7.46-7.31 (m, 10H), 7.00 (d, J=1.6 Hz, 1H),6.89 (d, J=2.0 Hz, 1H), 5.78-5.44 (m, 1H), 5.30-5.08 (m, 4H), 4.70 (brs, 1H), 4.35-4.20 (m, 3H), 4.08-3.79 (m, 2H), 3.72-3.13 (m, 7H),3.12-2.64 (m, 4H), 2.01-1.71 (m, 5H), 1.46 (s, 9H), 1.26-1.23 (m, 3H).

Step B: benzyl(2S)-4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-1-[(2R)-pyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)iperazine-1-carboxylate.To a solution of benzyl(2S)-4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-1-[(2R)-1-tert-butoxycarbonylpyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(450 mg, 537 umol, 1 eq) in DCM (600 uL) was added TFA (918 mg, 8.05mmol, 596 uL, 15 eq) at 0° C. under nitrogen atmosphere. The mixture wasstirred at 25° C. for 1 hour. Then the mixture was concentrated undervacuum. Compound benzyl(2S)-4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-1-[(2R)-pyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(700 mg, crude, TFA) was obtained as a yellow oil.

Step C: benzyl(2S)-4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-1-[(2R)-1-methylpyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.A mixture of benzyl(2S)-4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-1-[(2R)-pyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(650 mg, 763 umol, 1 eq, TFA), formaldehyde (310 mg, 3.81 mmol, 284 uL,5 eq. 37% in water) and AcOH (45.8 mg, 763 umol, 43.6 uL, 1 eq) in MeOH(15 mL) was stirred at 25° C. for 0.5 h. Then NaBH₃CN (120 mg, 1.91mmol, 2.5 eq) was added and the mixture was stirred at 25° C. for 1hour. The mixture was quenched with H₂O (10 mL) at 0° C., then extractedwith ethyl acetate (3×15 mL), washed with brine (1×15 mL), dried overNa₂SO₄, filtered and concentrated under vacuum. The residue was purifiedby reversed phase flash [water (0.1% FA)/acetonitrile]. The desiredfractions were collected and neutralized to pH=7 with saturated NaHCO₃solution and extracted with ethyl acetate (2×50 mL). The separatedorganic layer was dried over sodium sulfate, filtered and concentratedunder vacuum. Compound benzyl(2S)-4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-1-[(2R)-1-methylpyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(260 mg, 339 umol, two steps 68% yield, 97.9% purity) was obtained as ayellow solid.

Step D:2-[(2S)-4-[7-(3-hydroxy-1-naphthyl)-2-[(1R)-1-[(2R)-1-methylpyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.NH₃ was bubbled into MeOH (100 mL) at −60° C. for 20 minutes. To asolution of benzyl(2S)-4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-1-[(2R)-1-methylpyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(260 mg, 346 umol, 1 eq) in MeOH (15 mL) was added Pd/C (200 mg, 10%purity) and above mixture (NH₃·MeOH, 15 mL) under N₂. The suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred under H₂ (15 psi) at 25° C. for 1 hour. The catalyst wasfiltered off and concentrated under vacuum. Compound2-[(2S)-4-[7-(3-hydroxy-1-naphthyl)-2-[(1R)-1-[(2R)-1-methylpyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(180 mg, 300 umol, 87% yield, 88.0% purity) was obtained as a yellowoil. LCMS [ESI, M+1]: 528.

Step E:2-[(2S)-4-[7-(3-hydroxy-1-naphthyl)-2-[(1R)-1-[(2R)-1-methylpyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a mixture of2-[(2S)-4-[7-(3-hydroxy-1-naphthyl)-2-[(1R)-1-[(2R)-1-methylpyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(180 mg, 341 umol, 1 eq) and TEA (345 mg, 3.41 mmol, 475 uL, 10 eq) inDCM (8 mL) was added prop-2-enoyl chloride (30.9 mg, 341 umol, 27.8 uL,1 eq) in portion at −40° C. and the mixture was stirred at −40° C. for30 min. The reaction mixture was quenched with NaHCO₃ saturated solution(2 mL) at 0° C., and then extracted with CH₂Cl₂ (2×30 mL). The combinedorganic layers were washed with brine (1×30 mL), dried over sodiumsulfate, filtered and concentrated under vacuum to give a residue. Theresidue was purified by column chromatography (Al₂O₃; Ethylacetate/Methanol=20/1 to 3/1). The residue was purified by prep-HPLC(column: Phenomenex Gemini 150*25 mm*10 um; mobile phase: [water (0.05%ammonia hydroxide v/v)-ACN]; B %: 42%-72%, 12 min). Title compound2-[(2S)-4-[7-(3-hydroxy-1-naphthyl)-2-[(1R)-1-[(2R)-1-methylpyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 348, 23.5 mg, 39.9 umol, 12% yield, 99.0% purity) was obtainedas a white solid. LCMS [ESI, M+1]: 582.

SFC condition: “OJ-3S_3_5_40_3 ML Column: Chiralcel OJ-3 100×4.6 mmI.D., 3 um Mobile phase: methanol (0.05% DEA) in CO₂ from 5% to 40% Flowrate: 3 mL/min Wavelength: 220 nm”.

¹H NMR (400 MHz, methanol-d₄) δ=8.09 (d, J=8.4 Hz, 1H), 7.64 (d, J=8.0Hz, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.32-7.23 (m, 1H), 6.98-6.74 (m, 3H),6.31 (br d, J=16.4 Hz, 1H), 5.85 (br d, J=10.4 Hz, 1H), 5.27-5.15 (m,1H), 5.11 (br s, 1H), 4.62 (br s, 1H), 4.33-4.00 (m, 5H), 3.75-3.38 (m,2H), 3.27-2.81 (m, 7H), 2.75-2.62 (m, 1H), 2.55 (s, 3H), 2.47-2.31 (m,1H), 2.11-1.96 (m, 1H), 1.86-1.69 (m, 3H), 1.34 (d, J=6.4 Hz, 3H).

Example 349

2-((S)-1-acryloyl-4-(7-(3-fluoro-2,6-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step 1: 2-bromo-6-fluoro-3-methyl-benzaldehyde. To a solution of2-bromo-4-fluoro-1-methyl-benzene (10 g, 52.9 mmol, 1 eq) in THF (200mL) was added LDA (2 M in toluene, 31.7 mL, 1.2 eq) at −78° C. undernitrogen atmosphere. After stirred at −78° C. for 2 hours, a solution ofDMF (4.64 g, 63.5 mmol, 4.88 mL, 1.2 eq) was added at −78° C. Themixture was warmed up to 25° C. carefully and stirred for 0.5 hours. Themixture was quenched with water (5 mL) and the mixture was diluted withpetroleum ether/ethyl acetate (50 mL/5 mL) and water (50 mL). Theseparated organic layer was dried over sodium sulfate, filtered andconcentrated under vacuum. Compound2-bromo-6-fluoro-3-methyl-benzaldehyde (11.5 g, 52.9 mmol, 100% yield)was obtained as a colorless oil.

Step 2: (2-bromo-6-fluoro-3-methyl-phenyl methanol. To a solution of2-bromo-6-fluoro-3-methyl-benzaldehyde (11.5 g, 52.9 mmol, 1 eq) in MeOH(100 mL) was added NaBH₄ (2.20 g, 58.2 mmol, 1.1 eq) at 0° C. Themixture was stirred at 25° C. for 0.5 hour. The mixture was quenchedwith water at 0° C. and the mixture was concentrated under vacuum. Theresidue was purified by column chromatography over silica gel (petroleumether/ethyl acetate 50/1 to 3/1). The desired fractions were collectedand concentrated under vacuum. Compound(2-bromo-6-fluoro-3-methyl-phenyl)methanol (8.5 g, 38.4 mmol, 73% yield,99% purity) was obtained as a white solid LCMS [ESI, M−17]: 201.

¹H NMR (400 MHz, chloroform-d) δ=7.20 (dd, J=6.4, 8.4 Hz, 1H), 6.98 (t,J=8.8 Hz, 1H), 4.88 (d, J=2.0 Hz, 2H), 2.41 (s, 3H), 2.35-2.11 (m, 1H).

Step 3: 3-bromo-2-(bromomethyl)-1-fluoro-4-methyl-benzene. To a mixtureof (2-bromo-6-fluoro-3-methyl-phenyl)methanol (5 g, 22.8 mmol, 1 eq) inTHF (100 mL) was added PBr₃ (12.4 g, 45.6 mmol, 2 eq) in portions at 0°C. After stirred at 25° C. for 1 hour, the mixture was concentratedunder vacuum. The residue was diluted with ethyl acetate (100 mL) andwashed with ice water (1×50 mL), 10% aqueous sodium bicarbonate solution(2×50 mL) and brine (1×20 mL). The separated organic layer was driedover sodium sulfate, filtered and concentrated under vacuum. The residuewas purified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=1/0 to 10/1). Compound3-bromo-2-(bromomethyl)-1-fluoro-4-methyl-benzene (5.6 g, 19.9 mmol, 87%yield) was obtained as a colorless oil.

¹H NMR (400 MHz, chloroform-d) δ=7.20 (dd, J=6.4, 8.0 Hz, 1H), 6.97 (t,J=8.8 Hz, 1H), 4.70 (d, J=2.0 Hz, 2H), 2.41 (s, 3H).

Step 4: 3-bromo-1-fluoro-2,4-dimethyl-benzene. To a solution of3-bromo-2-(bromomethyl)-1-fluoro-4-methyl-benzene (5.6 g, 19.9 mmol, 1eq) in DMF (50 mL) was added NaBH₄ (1.50 g, 39.7 mmol, 2 eq) and AgNO₃(6.75 g, 39.7 mmol, 6.68 mL, 2 eq) at 25° C. The mixture was stirred at25° C. for 0.5 hour. The reaction mixture was diluted with water (20 mL)and extracted with ethyl acetate (50 mL×3). The combined organic layerswere washed with brine (20 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by reversed phase flash [water (0.1% formicacid)/acetonitrile)]. The mixture was concentrated under reducedpressure. Compound 3-bromo-1-fluoro-2,4-dimethyl-benzene (2.1 g, 9.93mmol, 50% yield, 96% purity) was obtained as a colorless oil.

¹H NMR (400 MHz, chloroform-d) δ=7.05 (dd, J=6.0, 8.4 Hz, 1H), 6.91 (t,J=8.8 Hz, 1H), 2.38 (s, 3H), 2.35 (d, J=2.4 Hz, 3H).

Step A: tert-Butyl(2S)-2-(cyanomethyl)-4-[7-(3-fluoro-2,6-dimethyl-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.A mixture of tert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 1.06 mmol, 1 eq), 3-bromo-1-fluoro-2,4-dimethyl-benzene (430mg, 2.12 mmol, 2 eq), RuPhos-Pd-G3 (177 mg, 212 umol, 0.2 eq), Cs₂CO₃(863 mg, 2.65 mmol, 2.5 eq) in toluene (10 mL) was degassed and purgedwith N₂ for 3 times, and then the mixture was stirred at 70° C. for 12hours under N₂ atmosphere. The reaction mixture was diluted with water(20 mL) and extracted with ethyl acetate (20 mL×3). The combined organiclayers were washed with brine (20 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by column chromatography (Al₂O₃, ethyl acetate/methanol=100/1to 10/1) and further purified by reversed phase flash [water (0.1%formic acid)/acetonitrile)]. The mixture was adjusted pH=7 withsaturated NaHCO₃ aqueous solution and extracted with ethyl acetate (20mL×3). The combined organic layers were washed with brine (20 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure. Compoundtert-Butyl(2S)-2-(cyanomethyl)-4-[7-(3-fluoro-2,6-dimethyl-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(20 mg, 28.6 umol, 3% yield, 85% purity) was obtained as a yellow oil.LCMS [ESI, M+1]: 594.

Step B:2-[(2S)-4-[7-(3-fluoro-2,6-dimethyl-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-2-(cyanomethyl)-4-[7-(3-fluoro-2,6-dimethyl-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(20 mg, 33.7 umol, 1 eq) in DCM (100 uL) was added TFA (576 mg, 505umol, 37.4 uL, 15 eq). After stirred at 25° C. for 1 hour, the reactionmixture was concentrated under vacuum. Compound2-[(2S)-4-[7-(3-fluoro-2,6-dimethyl-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(20.5 mg, 33.7 umol, 100% yield, TFA) was obtained as a yellow oil.

Step C:2-[(2S)-4-[7-(3-fluoro-2,6-dimethyl-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(3-fluoro-2,6-dimethyl-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(20.5 mg, 33.7 umol, 1 eq, TFA) in DCM (1 mL) was added TEA (34.1 mg,337 umol, 46.9 uL, 10 eq) at −40° C. Then prop-2-enoyl chloride (3.05mg, 33.7 umol, 2.75 uL, 1 eq) in DCM (1 mL) was added dropwised and themixture was stirred at −40° C. for 1 hour. The reaction mixture wasquenched with saturated NaHCO₃ aqueous solution (0.1 mL) andconcentrated under vacuum. The residue was purified by prep-TLC (SiO₂,dichloromethane/methanol=10/1) and further purified by prep-HPLC(column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water(0.225% FA)-ACN]; B %: 16%-43%, 9 min). Title compound2-[(2S)-4-[7-(3-fluoro-2,6-dimethyl-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 349, 0.39 mg, 0.693 umol, 2% yield, 97.3% purity) was obtainedas a colorless solid. LCMS [ESI, M+1]: 548.

¹H NMR (400 MHz, chloroform-d) δ=7.06-6.92 (m, 1H), 6.84 (t, J=8.8 Hz,1H), 6.70-6.49 (m, 1H), 6.42 (d, J=15.2 Hz, 1H), 5.85 (d, J=10.4 Hz,1H), 5.09 (br s, 1H), 4.60 (br s, 1H), 4.39-4.27 (m, 1H), 4.25-3.83 (m,5H), 3.75-3.22 (m, 5H), 3.19-2.47 (m, 10H), 2.34-2.21 (m, 6H), 2.21-1.89(m, 4H).

Example 350

2-((S)-1-acryloyl-4-(7-(3-hydroxynaphthalen-1-yl)-2-(((R)-1-methylpyrrolidin-3-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-2-yl)acetonitrile

Step A: tert-butyl(2S)-4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.A mixture of 3-benzyloxy-1-bromo-naphthalene (Intermediate 29, 1.01 g,3.21 mmol, 1.3 eq), tert-butyl(2S)-2-(cyanomethyl)-4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(Intermediate 66, 1 g, 2.47 mmol, 1 eq), Cs₂CO₃ (2.01 g, 6.18 mmol, 2.5eq), RuPhos (230 mg, 494 umol, 0.2 eq) and Pd₂(dba)₃ (452 mg, 494 umol,0.2 eq) in toluene (50 mL) was degassed and purged with N₂ for 3 times,and then the mixture was stirred at 90° C. for 5 hours under N₂atmosphere. The reaction mixture was diluted with water (50 mL) andextracted with ethyl acetate (50 mL×3). The combined organic layers werewashed with brine (20 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give a residue. The residue was purified bycolumn chromatography (SiO₂, Petroleum ether/Ethyl acetate 100/1 to3/1). Compound tert-butyl(2S)-4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(1.2 g, 1.71 mmol, 69% yield, 91% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 637.

Step B: tert-butyl(2S)-4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.To a solution of tert-butyl(2S)-4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(1.2 g, 1.88 mmol, 1 eq) in ethyl acetate (50 mL) was added m-CPBA (382mg, 1.88 mmol, 85% purity, 1 eq) at 0° C. After stirred at 0° C. for 0.5hour, the reaction mixture was quenched with saturated Na₂S₂O₃ aqueoussolution (20 mL), and then extracted with ethyl acetate (50 mL×3). Thecombined organic layers were washed with brine (50 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (SiO₂, Ethylacetate/MeOH=100/1 to 10/1). Compound tert-butyl(2S)-4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(900 mg, 1.30 mmol, 69% yield, 94% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 653.

Step C: tert-butyl (2S)-4-[7-(3-benzyloxy-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.To a solution of tert-butyl(2S)-4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(793 mg, 1.22 mmol, 1 eq) in toluene (10 mL) was added t-BuONa (350 mg,3.65 mmol, 3 eq) and [(3R)-1-methylpyrrolidin-3-yl]methanol (420 mg,3.65 mmol, 3 eq) at 0° C. The mixture was stirred at 0° C. for 0.5 hour.The reaction mixture was diluted with water (30 mL) and extracted withethyl acetate (50 mL×3). The combined organic layers were washed withbrine (20 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=10/1 to 0/1).Compound tert-butyl (2S)-4-[7-(3-benzyloxy-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(700 mg, 944 umol, 78% yield, 95% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 704.

Step D: tert-butyl(2S)-2-(cyanomethyl)-4-[7-(3-hydroxy-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.NH₃ was bubbled into MeOH (100 mL) at −60° C. for 10 minutes. To asolution of tert-butyl(2S)-4-[7-(3-benzyloxy-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(700 mg, 994 umol, 1 eq) in MeOH (20 mL) was added dry Pd/C (300 mg, 10%purity) and the above NH₃·MeOH solution (20 mL) under N₂. The suspensionwas degassed under vacuum and purged with H₂ several times. The mixturewas stirred under H₂ (15 psi) at 25° C. for 1 hour. The catalyst wasfiltered off and the filtrate was concentrated under vacuum. The residuewas purified by reversed phase flash [water (0.1% formicacid)/acetonitrile)]. The mixture was adjusted pH=7 with saturatedNaHCO₃ aqueous solution and extracted with ethyl acetate (20 mL×3). Thecombined organic layers were washed with brine (20 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give theproduct Compound tert-butyl(2S)-2-(cyanomethyl)-4-[7-(3-hydroxy-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(400 mg, 619 umol, 62% yield, 95% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 614.

¹H NMR (400 MHz, chloroform-d) δ=8.02 (d, J=8.4 Hz, 1H), 7.62 (d, J=8.4Hz, 1H), 7.38 (t, J=7.2 Hz, 1H), 7.29 (t, J=7.2 Hz, 1H), 6.88 (d, J=2.0Hz, 1H), 6.70 (d, J=2.0 Hz, 1H), 4.57 (br s, 1H), 4.36-4.22 (m, 2H),4.17-4.14 (m, 1H), 4.02 (br d, J=13.6 Hz, 2H), 3.85 (br d, J=12.8 Hz,1H), 3.47-3.08 (m, 3H), 3.07-2.64 (m, 12H), 2.56 (s, 3H), 2.27-2.14 (m,1H), 1.89-1.75 (m, 1H), 1.52 (s, 9H).

Step E:2-[(2S)-4-[7-(3-hydroxy-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-2-(cyanomethyl)-4-[7-(3-hydroxy-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(400 mg, 651 umol, 1 eq) in DCM (500 uL) was added TFA (743 mg, 6.52mmol, 482 uL, 10 eq). After stirred at 25° C. for 1 hour, the reactionmixture was concentrated under vacuum. Compound2-[(2S)-4-[7-(3-hydroxy-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(409 mg, crude, TFA) was obtained as a brown oil and used next stepdirectly without purification. LCMS [ESI, M+1]: 514.

Step F:2-[(2S)-4-[7-(3-hydroxy-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(3-hydroxy-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(409 mg, 651 umol, 1 eq, TFA) in DCM (10 mL) was added TEA (659 mg, 6.52mmol, 907 uL, 10 eq) at 0° C. After addition, prop-2-enoyl chloride(53.1 mg, 586 umol, 47.8 uL, 0.9 eq) in DCM (1 mL) was added dropwise at−40° C. The resulting mixture was stirred at −40° C. for 0.5 hour. Thereaction mixture was quenched with saturated NaHCO₃ aqueous solution (1mL) and extracted with ethyl acetate (10 mL×3). The combined organiclayers were washed with brine (10 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by column chromatography (SiO₂, Ethyl acetate/MeOH 100/1 to5/1) and further purified by prep-HPLC (column: Boston Green ODS 150*305 u; mobile phase: [water (0.225% FA)-ACN]; B %: 11%-41%, 10 min). Themixture was adjusted pH=8 with saturated NaHCO₃ aqueous solution andextracted with dichloromethane (50 mL×3). The combined organic layerswere washed with brine (20 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. Title compound2-[(2S)-4-[7-(3-hydroxy-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 350, 25.5 mg, 39.9 umol, 6% yield, 89% purity) was obtained asa brown solid. LCMS [ESI, M+1]: 568.

¹H NMR (400 MHz, Acetic acid-d₄) δ=8.07 (d, J=8.4 Hz, 1H), 7.66 (d,J=8.0 Hz, 1H), 7.39 (t, J=7.2 Hz, 1H), 7.29 (t, J=7.2 Hz, 1H), 6.96 (d,J=2.0 Hz, 1H), 6.87 (d, J=1.6 Hz, 1H), 6.75 (br s, 1H), 6.38 (d, J=16.8Hz, 1H), 5.87 (d, J=10.0 Hz, 1H), 5.23-5.01 (m, 1H), 4.98-4.49 (m, 4H),4.43 (s, 1H), 4.33 (s, 2H), 4.23-4.00 (m, 1H), 3.99-3.51 (m, 5H),3.50-3.23 (m, 4H), 3.17-2.91 (m, 8H), 2.63-2.24 (m, 1H).

Example 351

2-[(2S)-4-[2-(1H-imidazol-2-ylmethoxy)-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step 1: ethyl 1-tetrahydropyran-2-ylimidazole-2-carboxylate. A mixtureof ethyl 1H-imidazole-2-carboxylate (5 g, 35.7 mmol, 1 eq), DHP (33.0 g,392 mmol, 35.9 mL, 11.0 eq) and PTSA·H₂O (400 mg, 2.32 mmol, 6.51 e-2eq) in THF (100 mL) was stirred at 60° C. (oil bath temperature) for 16hours. Upon completion, the mixture was concentrated under vacuum andthen diluted with ethyl acetate (100 mL) and water (100 mL). Theseparated organic layer was washed with brine (1×100 mL), dried oversodium sulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography over silica gel (petroleum ether/ethylacetate 20/1 to 1/1) to give ethyl1-tetrahydropyran-2-ylimidazole-2-carboxylate (6.2 g, 26.0 mmol, 73%yield, 94% purity) as a light yellow oil.

¹H NMR (400 MHz, chloroform-d) δ=7.40 (d, J=0.8 Hz, 1H), 7.16 (d, J=0.8Hz, 1H), 6.21 (dd, J=2.0, 10.0 Hz, 1H), 4.39 (dq, J=0.8, 7.2 Hz, 2H),4.20-4.10 (m, 1H), 3.71 (dt, J=2.8, 11.6 Hz, 1H), 2.13-2.03 (m, 1H),2.03-1.88 (m, 1H), 1.80-1.55 (m, 4H), 1.42 (t, J=7.2 Hz, 3H).

Step 2: (1-tetrahydropyran-2-ylimidazol-2-yl)methanol. A solution ofethyl 1-tetrahydropyran-2-ylimidazole-2-carboxylate (2 g, 8.92 mmol, 1eq) in THF (40 mL) was added LiAlH₄ (758 mg, 20.0 mmol, 2.24 eq) in 3portions at 0° C. The mixture was stirred at 0° C. for 1 hour. Uponcompletion, the mixture was quenched with saturated aqueous Na₂SO₄ (2.89mL), filtered and the filtrate was concentrated. The residue waspurified by chromatography (Al₂O₃, EtOAc/MeOH 1/0 to 10/1) to give(1-tetrahydropyran-2-ylimidazol-2-yl)methanol (1.57 g, 7.75 mmol, 87%yield, 90% purity) as a yellow oil.

¹H NMR (400 MHz, methanol-d₄) δ=7.27 (d, J=1.6 Hz, 1H), 6.89 (d, J=1.2Hz, 1H), 5.54 (dd, J=2.4, 10.0 Hz, 1H), 4.74-4.61 (m, 2H), 4.15-3.99 (m,1H), 3.76-3.68 (m, 1H), 2.06-1.88 (m, 3H), 1.84-1.60 (m, 3H).

Step A: benzyl(2S)-2-(cyanomethyl)-4-[7-(1-naphthyl)-2-[(1-tetrahydropyran-2-ylimidazol-2-yl)methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[2-methylsulfinyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(Intermediate 64, 380 mg, 654 umol, 1 eq) and(1-tetrahydropyran-2-ylimidazol-2-yl)methanol (238 mg, 1.31 mmol, 2 eq)in toluene (0.4 mL) was added t-BuONa (126 mg, 1.31 mmol, 2 eq) at 0° C.The mixture was stirred at 0° C. for 20 minutes. Upon completion, themixture was concentrated under vacuum. The residue was diluted withwater (10 mL) and extracted with EtOAc (2×20 mL). The organic layerswere dried over Na₂SO₄ and concentrated under vacuum. The residue waspurified by chromatography (SiO₂, PE/EtOAc 3/1 to 1/3) to give benzyl(2S)-2-(cyanomethyl)-4-[7-(1-naphthyl)-2-[(1-tetrahydropyran-2-ylimidazol-2-yl)methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(270 mg, 363.19 umol, 56% yield, 94% purity) as a yellow solid. LCMS[ESI, M+1]: 699.

Step B:2-[(2S)-4-[7-(1-naphthyl)-2-[(1-tetrahydropyran-2-ylimidazol-2-yl)methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.NH₃ was bubbled into MeOH (3 mL) at −40° C. for 10 minutes. A solutionof benzyl(2S)-2-(cyanomethyl)-4-[7-(1-naphthyl)-2-[(1-tetrahydropyran-2-ylimidazol-2-yl)methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(260 mg, 372 umol, 1 eq) in MeOH (3 mL) was added above solution, thenPd/C (100 mg, 10% purity) under N₂. The suspension was degassed undervacuum and purged with H₂ 6 times. The reaction was stirred under H₂ (15psi) at 28° C. for 1 hour. Upon completion, the mixture was filtered andthe filtrate was concentrated under vacuum to give2-[(2S)-4-[7-(1-naphthyl)-2-[(1-tetrahydropyran-2-ylimidazol-2-yl)methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(160 mg, 275 umol, 74% yield, 97% purity) as a yellow solid which wasused directly into the next step without further purification. LCMS[ESI, M+1]: 565.

Step C:2-[(2S)-4-[7-(1-naphthyl)-2-[(1-tetrahydropyran-2-ylimidazol-2-yl)methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(1-naphthyl)-2-[(1-tetrahydropyran-2-ylimidazol-2-yl)methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(160 mg, 283 umol, 1.00 eq) and DIEA (73.2 mg, 567 umol, 98.7 uL, 2.00eq) in DCM (3 mL) was added prop-2-enoyl chloride (38.5 mg, 425 umol,34.7 uL, 1.50 eq) dropwise at −40° C. The mixture was stirred at −40° C.for 10 minutes. Upon completion, to the mixture was added saturatedaqueous NaHCO₃ (1 mL) and water (3 mL). Layers were separated. Theaqueous phase was extracted with EtOAc (2×5 mL). The combined organiclayers were dried over Na₂SO₄ and concentrated under vacuum. The residuewas purified by column chromatography (Al₂O₃, EtOAc/MeOH 50/1 to 10/1)to give2-[(2S)-4-[7-(1-naphthyl)-2-[(1-tetrahydropyran-2-ylimidazol-2-yl)methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(80 mg, 101 umol, 36% yield, 78% purity) as a yellow solid. LCMS [ESI,M+1]: 619.

Step D:2-[(2S)-4-[2-(1H-imidazol-2-ylmethoxy)-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.A solution of2-[(2S)-4-[7-(1-naphthyl)-2-[(1-tetrahydropyran-2-ylimidazol-2-yl)methoxy]-6,8-dihydro-Sif-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(67 mg, 84.5 umol, 1 eq) and TsOH·H₂O (48.2 mg, 253 umol, 3 eq) in MeCN(1.5 mL) was stirred at 60° C. for 3 hours. Upon completion, the mixturewas quenched with saturated aqueous NaHCO₃ (1 mL) at 0° C. The residuewas purified by reversed-phase flash [water (0.1%NH₃·H₂O)/acetonitrile]. The desired fractions were collected andlyophilized. The crude product was purified by prep-HPLC (column:PhenomenexSynergi C18 150*30 mm*4 um; mobile phase: [water (0.225%FA)-ACN]; B %: 20%, 0-50%, 10.5 min). The desired fractions werecollected and lyophilized. to give title compound2-[(2S)-4-[2-(1H-imidazol-2-ylmethoxy)-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 351, 2.55 mg, 4.22 umol, 5.4% yield, 96% purity, FA) as a whitesolid. LCMS [ESI, M+1]: 535.

SFC Condition: Column: Chiralpak AS-3 50×4.6 mm I.D., 3 um, Mobilephase: methanol (0.05% DEA) in CO₂ from 5% to 40%, Flow rate: 3 mL/min,Wavelength: 220 nm

¹H NMR (400 MHz, chloroform-d) δ=8.26-8.20 (m, 1H), 7.92-7.82 (m, 1H),7.63 (d, J=8.4 Hz, 1H), 7.56-7.48 (m, 2H), 7.45 (t, J=8.0 Hz, 1H), 7.17(d, J=7.2 Hz, 1H), 7.08-6.99 (m, 2H), 6.69-6.52 (m, 1H), 6.46-6.32 (m,1H), 5.84 (br d, J=11.2 Hz, 1H), 5.56-5.44 (m, 2H), 5.24-4.90 (m, 1H),4.88-4.14 (m, 4H), 4.14-3.79 (m, 2H), 3.79-3.37 (m, 3H), 3.35-2.64 (m,4H), 2.61-2.49 (m, 1H).

Example 352

2-[(2S)-4-[7-(4-cyclopropyl-3-pyridyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

3-bromo-4-cyclopropyl-pyridine. A mixture of 3,4-dibromopyridine (3.0 g,12.7 mmol, 1.0 eq), cyclopropylboronic acid (1.09 g, 12.7 mmol, 1.0 eq),Pd(dppf)Cl₂ (927 mg, 1.27 mmol, 0.10 eq), K₃PO₄ (8.06 g, 38.0 mmol, 3.0eq) in DMF (15.0 mL) and H₂O (3.0 mL) was degassed and purged with N₂for 3 times, and then the mixture was stirred at 60° C. for 6 hrs underN₂ atmosphere. The organic solvent was washed with water (80.0 mL). Theaqueous phase was extracted with ethyl acetate (3×100 mL). Combineextracts were washed with brine (300 mL), dried with Na₂SO₄ the solventwas then removed under vacuum. The residue was purified by columnchromatography (SiO₂, Petroleum ether:Ethyl acetate=30:1 to 20:1).Compound 3-bromo-4-cyclopropyl-pyridine (630 mg, 3.17 mmol, 25% yield,99.6% purity) was obtained as a yellow oil. LCMS [ESI, M+1]: 198.

¹H NMR (400 MHz, CHLOROFORM-d) δ=8.69-8.61 (m, 1H), 8.39-8.32 (m, 1H),6.75-6.71 (m, 1H), 2.29-2.18 (m, 1H), 1.20-1.12 (m, 2H), 0.84-0.77 (m,2H).

Step A: tert-butyl(2S)-2-(cyanomethyl)-4-[7-(4-cyclopropyl-3-pyridyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.A mixture of tert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(Intermediate 66, 500 mg, 1.06 mmol, 1.0 eq),3-bromo-4-cyclopropyl-pyridine (315 mg, 1.59 mmol, 1.50 eq), Pd₂(dba)₃(97.09 mg, 106 umol, 0.10 eq), RuPhos (99.0 mg, 212 umol, 0.20 eq) andCs₂CO₃ (1.04 g, 3.18 mmol, 3.0 eq) in toluene (5.0 mL) was degassed andpurged with N₂ for 3 times, and then the mixture was stirred at 90° C.for 12 hrs under N₂ atmosphere. The organic solvent was washed withwater (15.0 mL). The aqueous phase was extracted with ethyl acetate(3×20 mL). Combine extracts were washed with brine (50.0 mL), dried withNa₂SO₄ the solvent was then removed under vacuum. The residue waspurified by reversed phase flash HPLC [C18, 0.1% NH₃·H₂O in water, 0-60%MeCN]. The obtained product was then concentrated, the aqueous wasextracted with EA (3×50 mL), the combined organic layer was dried overNa₂SO₄, filtered and concentrated. Compound tert-butyl(2S)-2-(cyanomethyl)-4-[7-(4-cyclopropyl-3-pyridyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(180 mg, 260 umol, 24.5% yield, 85% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]:589.

Step B:2-[(2S)-4-[7-(4-cyclopropyl-3-pyridyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-2-(cyanomethyl)-4-[7-(4-cyclopropyl-3-pyridyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(30.0 mg, 43.3 umol, 1.0 eq) in dioxane (1.0 mL) was added HCl·dioxane(4 M, 1.0 mL, 92.4 eq). The mixture was stirred at 25° C. for 30 minunder N₂ atmosphere. The organic solvent was removed under vacuum. Theobtained product was adjusted with saturated NaHCO₃ aqueous to pH˜8,then concentrated, the aqueous was extracted with ethyl acetate (3×10mL), the combined organic layer was dried over Na₂SO₄, filtered andconcentrated. The crude product2-[(2S)-4-[7-(4-cyclopropyl-3-pyridyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(30.0 mg, crude) was obtained as a yellow solid and used into the nextstep without further purification. LCMS [ESI, M+1]: 489.

Step C:2-[(2S)-4-[7-(4-cyclopropyl-3-pyridyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(4-cyclopropyl-3-pyridyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(30.0 mg, 61.4 umol, 1.0 eq) in DCM (1.50 mL) was added TEA (31.1 mg,307 umol, 42.7 uL, 5.0 eq) and prop-2-enoyl chloride (8.34 mg, 92.1umol, 7.51 uL, 1.50 eq) at −60° C. The mixture was stirred at −60° C.for 30 min under N₂ atmosphere. The reaction was quenched with methanol(6.0 mL) and was removed under vacuum. The residue was purified byprep-HPLC (column: Gemini 150*25 5 u; mobile phase: [water (0.05%ammonia hydroxide v/v)-ACN]; B %: 33%-63%, 12 min) and lyophilization.Title compound2-[(2S)-4-[7-(4-cyclopropyl-3-pyridyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 352, 2.71 mg, 4.97 umol, 8.1% yield, 99.5% purity) was obtainedas a white solid. LCMS [ESI, M+1]: 543.

¹H NMR (400 MHz, CHLOROFORM-d) δ=8.29 (s 1H), 8.26 (d, J=5.2 Hz, 1H),6.68 (d, J=5.2 Hz, 1H), 6.64-6.53 (m, 1H), 6.40 (dd, J=0.8 Hz, J=16.8Hz, 1H), 5.52 (d, J=10.4 Hz, 1H), 5.07 (br s, 1H), 4.39 (dd, J=4.8 Hz,J=10.4 Hz, 1H), 4.29-4.23 (m, 1H), 4.21-4.15 (m, 2H), 4.13-4.07 (m, 1H),4.00-3.95 (m, 1H), 3.57 (br s, 1H), 3.44-3.24 (m, 4H), 3.17-3.03 (m,2H), 2.94 (dd, J=8.8 Hz, J=16.8 Hz, 1H), 2.87-2.80 (m, 2H), 2.73-2.64(m, 1H), 2.49 (s, 3H), 2.35-2.22 (m, 3H), 2.11-2.00 (m, 1H), 1.89-1.76(m, 3H), 1.17-1.11 (m, 2H), 0.90-0.77 (m, 3H).

Example 353

1-[(3R)-3-methyl-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: tert-butyl(3R)-4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-3-methyl-piperazine-1-carboxylate.The solution of7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (1.5 g,5.10 mmol, 1 eq), tert-butyl (3R)-3-methylpiperazine-1-carboxylate (1.12g, 5.61 mmol, 1.1 eq), DIEA (1.32 g, 10.2 mmol, 1.78 mL, 2 eq) in NMP(30 mL) was stirred at 100° C. for 7 hours. Water (90 mL) was added intothe mixture. The resulting mixture was diluted with EtOAc (20 mL) andextracted with EtOAc (3×50 mL). The combined organic layers were washedwith brine (40 mL). The combined organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated under vacuum. The residuewas slurried with (PE:EtOAc=3:1, 20 mL) and filtered and the filter cakewas washed with (PE:EtOAc=3:1, 40 mL) to give tert-butyl(3R)-4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-3-methyl-piperazine-1-carboxylate(0.9 g, 1.73 mmol, 34% yield, 88.0% purity) as a gray solid. LCMS [ESI,M+1]: 458.

¹H NMR (400 MHz, chloroform-d) δ=7.38-7.27 (m, 5H), 4.28-4.18 (m, 1H),4.16-3.80 (m, 2H), 3.74 (br d, J=13.6 Hz, 1H), 3.68 (s, 2H), 3.65-3.52(m, 2H), 3.41-3.27 (m, 1H), 3.21-2.89 (m, 2H), 2.74-2.58 (m, 4H), 1.48(s, 9H), 1.23 (d, J=6.8 Hz, 3H).

Step B: tert-butyl(3R)-4-[7-benzyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate.To the solution of [(2S)-1-methylpyrrolidin-2-yl]methanol (566 mg, 4.91mmol, 583 uL, 2.5 eq) in THF (20 mL) was added NaH (157 mg, 3.93 mmol,60.0% purity, 2 eq) at 0° C. and stirred at 0° C. for 0.5 hour. Thentert-butyl(3R)-4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-3-methyl-piperazine-1-carboxylate(900 mg, 1.97 mmol, 1 eq) was added to the mixture. The reaction mixturewas heated to 70° C. for 12 hours in a tube under N₂. The mixture wasquenched by Water (15 mL). The mixture was diluted with EtOAc (10 mL)and extracted with EtOAc (3×50 mL). The combined organic layers werewashed with brine (40 mL). The combined organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated under vacuum. The residuewas purified by reversed phase flash column (ACN/Water (0.1% FA)=35%) togive tert-butyl(3R)-4-[7-benzyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate(680 mg, 1.14 mmol, 58% yield, 90.0% purity) as a brown solid. LCMS[ESI, M+1]: 537.

Step C: tert-butyl(3R)-3-methyl-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To the solution of tert-butyl(3R)-4-[7-benzyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate(680 mg, 1.27 mmol, 1 eq) in MeOH (14 mL) was added Pd(OH)₂/C (340 mg,10% purity) under N₂. The suspension was degassed under vacuum andpurged with H₂ several times. The mixture was stirred under H₂ (15 psi)at 40° C. for 4 hours. The reaction mixture was filtered, the filtercake was washed with MeOH (3×10 mL), and the fitrate was concentratedunder vacuum to give tert-butyl(3R)-3-methyl-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(540 mg, 1.09 mmol, 86% yield, 90.0% purity) as a brown solid which wasused for next step without further purification.

Step D: tert-butyl(3R)-3-methyl-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To the solution of tert-butyl(3R)-3-methyl-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(520 mg, 1.16 mmol, 1 eq), 1-bromonaphthalene (482 mg, 2.33 mmol, 324uL, 2 eq), RuPhos (109 mg, 233 umol, 0.2 eq) and Cs₂CO₃ (1.14 g, 3.49mmol, 3 eq) in toluene (11 mL) was added Pd₂(dba)₃ (107 mg, 116 umol,0.1 eq) under N₂. The suspension was degassed under vacuum and purgedwith N₂ several times. The mixture was stirred under N₂ at 105° C. for 7hours. Water (10 mL) was added into the mixture. The mixture was dilutedwith EtOAc (10 mL) and extracted with EtOAc (3×20 mL). The combinedorganic layers were washed with brine (20 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under vacuum. The residue was purifiedby silica gel chromatography (PE:EtOAc from 5:1 to 0:1). Then theresidue was purified by reversed phase flash column (ACN/Water (0.1% FA)61%). Compound tert-butyl(3R)-3-methyl-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(330 mg, 547 umol, 47% yield, 95.0% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 573.

¹H NMR (400 MHz, chloroform-d) δ=8.26-8.18 (m, 1H), 7.89-7.84 (m, 1H),7.60 (d, J=8.4 Hz, 1), 7.54-7.47 (m, 2H), 7.43 (t, J=7.6 Hz, 1H), 7.14(d, J=7.2 Hz, 1H), 4.41 (dd, J=5.2, 10.4 Hz, 1H), 4.26 (s, 3H),4.18-4.14 (m, 1H), 4.03-3.68 (m, 2H), 3.45-3.00 (m, 6H), 2.84 (br s,2H), 2.69 (br d, J=6.4 Hz, 1H), 2.50 (s, 3H), 2.35-2.24 (m, 1H),2.12-2.06 (m, 1H), 1.91-1.70 (m, 4H), 1.50 (s, 9H), 1.32-1.27 (m, 3H).

Step E:4-[(2R)-2-methylpiperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine.The mixture of tert-butyl(3R)-3-methyl-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(330 mg, 576 umol, 1 eq) and TFA (657 mg, 5.76 mmol, 427 uL, 10 eq) wasstirred at 30° C. for 40 mins. The mixture was concentrated under vacuumto give4-[(2R)-2-methylpiperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(340 mg, crude, TFA) as a brown oil which was used for next step withoutfurther purification.

Step F:1-[(3R)-3-methyl-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one.To the solution of4-[(2R)-2-methylpiperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(340 mg, crude, TFA), TEA (586 mg, 5.80 mmol, 807 uL) in DCM (6 mL) wasadded prop-2-enoyl chloride (78.7 mg, 869 umol, 70.9 uL) at −40° C., themixture was stirred at −40° C. for 0.5 hour. The mixture was quenched bysaturated NaHCO₃ (2 mL). The mixture was diluted with EtOAc (5 mL) andextracted with EtOAc (10 mL). The organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated under vacuum. The residue was purifiedby prep-HPLC (column: Gemini 150*25 5 u; mobile phase: [water (0.05%ammonia hydroxide v/v)-ACN]; B %: 55%-85%, 12 min) to give titlecompound1-[(3R)-3-methyl-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(EXAMPLE 353, 85.5 mg, 162 umol, two steps 28% yield, 99.8% purity) as awhite solid. LCMS [ESI, M+1]: 527.

¹H NMR (400 MHz, chloroform-d) δ 8.23 (br d, J=9.2 Hz, 1H), 7.90-7.84(m, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.55-7.47 (m, 2H), 7.44 (t, J=7.6 Hz,1H), 7.15 (d, J=7.2 Hz, 1H), 6.70-6.52 (m, 1H), 6.37 (dd, J=1.6, 16.8Hz, 1H), 5.77 (br d, J=10.0 Hz, 1H), 4.66-4.31 (m, 3H), 4.27 (s, 2H),4.14 (dd, J=6.8, 10.4 Hz, 1H), 4.02-3.73 (m, 2H), 3.64-3.25 (m, 4H),3.24-2.99 (m, 2H), 2.86 (br s, 2H), 2.74-2.63 (m, 1H), 2.49 (s, 3H),2.34-2.24 (m, 1H), 2.13-2.00 (m, 1H), 1.90-1.74 (m, 3H), 1.28 (br d,J=4.4 Hz, 3H).

Example 354

1-[3,3-dimethyl-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: tert-butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-3,3-dimethyl-piperazine-1-carboxylate.The solution of7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (1.5 g,5.10 mmol, 1 eq) and tert-butyl 3,3-dimethylpiperazine-1-carboxylate(4.37 g, 20.4 mmol, 4 eq) was stirred at 130° C. for 22 hours. Theresidue was used directly to purify. The residue was purified by silicagel chromatography (PE:EtOAc from 1:0 to 10:1). Then the residue waspurified by prep-HPLC (column: Phenomenex Synergi Max-RP 250*80 mm*10um; mobile phase: [water (0.225% FA)-ACN]; B %: 30%-60%, 35 min, 60%min) to give tert-butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-3,3-dimethyl-piperazine-1-carboxylate(1 g, 2.12 mmol, 42% yield, 100% purity) as a yellow solid LCMS [ESI,M+1]: 472.

¹H NMR (400 MHz, chloroform-d) δ=7.39-7.28 (m, 5H), 4.01 (t, J=5.6 Hz,2H), 3.69 (s, 2H), 3.55-3.44 (m, 6H), 2.78-2.66 (m, 4H), 1.51 (s, 6H),1.48 (s, 9H).

Step B: tert-butyl4-[7-benzyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3,3-dimethyl-piperazine-1-carboxylate.To the solution of [(2S)-1-methylpyrrolidin-2-yl]methanol (610 mg, 5.30mmol, 629 uL, 2.5 eq) in THF (20 mL) was added NaH (169 mg, 4.24 mmol,60% purity, 2 eq) at 0° C. and stirred at 0° C. for 0.5 hour. Thentert-butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-3,3-dimethyl-piperazine-1-carboxylate(1 g, 2.12 mmol, 1 eq) was added to the mixture. The reaction mixturewas heated to 70° C. for 12 hours in a tube under N₂. The reactionmixture was quenched by Water (10 mL). The mixture was diluted withEtOAc (10 mL) and extracted with EtOAc (2×30 mL). The combined organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by prep-HPLC (column: Phenomenex lunaC18 250*50 mm*10 um; mobile phase: [water (0.225% FA)-ACN]; B %:25%-50%, 30; 79% min) to give tert-butyl4-[7-benzyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3,3-dimethyl-piperazine-1-carboxylate(980 mg, 1.69 mmol, 80% yield, 95.0% purity) as a yellow oil. LCMS [ESI,M+1]: 551.

Step C: tert-butyl3,3-dimethyl-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To the solution of tert-butyl4-[7-benzyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3,3-dimethyl-piperazine-1-carboxylate(980 mg, 1.78 mmol, 1 eq) in MeOH (20 mL) was added Pd(OH)₂/C (500 mg,10% purity) under N₂. The suspension was degassed under vacuum andpurged with H₂ several times. The mixture was stirred under H₂ (15 psi)at 40° C. for 4 hours. The mixture was filtered, the filter cake waswashed with MeOH (3×10 mL). The filtrate was concentrated under vacuumto give tert-butyl3,3-dimethyl-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(780 mg, 1.69 mmol, 95% yield, 100% purity) as a colorless oil which wasused for next step without further purification. LCMS [ESI, M+1]: 461.

Step D: tert-butyl3,3-dimethyl-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To the solution of tert-butyl3,3-dimethyl-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(400 mg, 868 umol, 1 eq), 1-bromonaphthalene (360 mg, 1.74 mmol, 241 uL,2 eq), Cs₂CO₃ (849 mg, 2.61 mmol, 3 eq) and RuPhos (81.0 mg, 174 umol,0.2 eq) in toluene (8 mL) was added Pd₂(dba)₃ (79.5 mg, 86.8 umol, 0.1eq) under N₂. The suspension was degassed under vacuum and purged withN₂ several times. The mixture was stirred under N₂ at 95° C. for 8hours. Water (10 mL) was added into the mixture. The mixture was dilutedwith EtOAc (10 mL) and extracted with EtOAc (2×20 mL). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by silica gelchromatography (PE:EtOAc=10:1-0:1). Then the residue was purified byreversed phase flash column (ACN/Water (0.1% FA)=52%) to give tert-butyl3,3-dimethyl-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(210 mg, 340 umol, 39% yield, 95.0% purity) as a white solid. LCMS [ESI,M+1]: 587.

¹H NMR (400 MHz, chloroform-d) δ=8.22 (dd, J=3.2, 6.4 Hz, 1H), 7.87-7.82(m, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.51-7.45 (m, 2H), 7.42 (t, J=7.6 Hz,1H), 7.15 (d, J=7.6 Hz, 1H), 4.39-4.27 (m, 2H), 4.12-4.05 (m, 3H),3.60-3.26 (m, 6H), 3.14 (br t, J=7.6 Hz, 1H), 2.79 (br s, 2H), 2.74-2.65(m, 1H), 2.53 (s, 3H), 2.39-2.28 (m, 1H), 2.05-2.00 (m, 1H), 1.92-1.70(m, 4H), 1.58 (br d, J=4.0 Hz, 6H), 1.49 (s, 9H).

Step E:4-(2,2-dimethylpiperazin-1-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine.The solution of tert-butyl3,3-dimethyl-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(210 mg, 358 umol, 1 eq) and TFA (408 mg, 3.58 mmol, 265 uL, 10 eq) wasstirred at 30° C. for 0.5 hour. The mixture was concentrated undervacuum to give4-(2,2-dimethylpiperazin-1-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(210 mg, crude, TFA) as a brown oil which was used for next step withoutfurther purification.

Step F:1-[3,3-dimethyl-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one.To the solution of4-(2,2-dimethylpiperazin-1-yl)-2-[[(2S)-1-methylpyrimidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(210 mg, crude, TFA) and TEA (531 mg, 5.24 mmol, 730 uL) in DCM (4 mL)was added prop-2-enoyl chloride (47.5 mg, 524 umol, 42.8 uL) at −40° C.,the mixture was stirred at −40° C. for 0.5 hour. The mixture wasquenched by water (2 mL). The mixture was diluted with EtOAc (5 mL) andextracted with EtOAc (10 mL). The organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated under vacuum. The residue was purifiedby prep-HPLC (column: Gemini 150*25 5 u; mobile phase: [water (0.05%ammonia hydroxide v/v)-ACN]; B %: 73%-100%, 12 min) to give titlecompound1-[3,3-dimethyl-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(EXAMPLE 354, 104 mg, 189 umol, 53% yield, 98.6% purity) as a whitesolid. LCMS [ESI, M+1]: 541.

¹H NMR (400 MHz, chloroform-d) δ=8.26-8.18 (m, 1H), 7.85 (dd, J=3.2, 6.4Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.48 (dd, J=3.2, 6.4 Hz, 2H), 7.42 (t,J=7.6 Hz, 1H), 7.15 (br d, J=7.2 Hz, 1H), 6.65-6.52 (m, 1H), 6.48-6.33(m, 1H), 5.79-5.70 (m, 1H), 4.37-4.26 (m, 2H), 4.21 (br t, J=5.6 Hz,1H), 4.17-4.06 (m, 3H), 3.80 (s, 1H), 3.78-3.69 (m, 2H), 3.61 (s, 1H),3.39 (br s, 2H), 3.13 (br t, J=7.6 Hz, 1H), 2.80 (br s, 2H), 2.73-2.65(m, 1H), 2.52 (s, 3H), 2.37-2.28 (m, 1H), 2.09-1.99 (m, 1H), 1.94-1.68(m, 3H), 1.62 (br s, 6H).

Example 355

1-[4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(3-methoxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: tert-butyl4-(7-benzyl-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate. To a solution of7-benzyl-4-chloro-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(5.0 g, 16.4 mmol, 1.0 eq) and tert-butyl piperazine-1-carboxylate (4.57g, 24.5 mmol, 1.50 eq) in DMSO (20.0 mL) was added DIEA (6.34 g, 49.1mmol, 8.54 mL, 3.0 eq). The mixture was stirred at 60° C. for 5 hours.After completion, the mixture was added water (200 mL) and extractedwith EA (200 ml×3). The organic layer was washed with brine (500 mL),dried over Na₂SO₄, filtered and concentrated. The obtained product waspurified by column chromatography (SiO₂, PE:EA 50:1-5:1) to givetert-butyl4-(7-benzyl-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (7.0 g, 15.4 mmol, 93 yield) as light brownsolid. LCM [ESI, M+7]: 456.

¹H NMR (400 MHz, Chloroform-d) δ 7.40-7.27 (m, 5H), 3.68 (s, 2H), 3.58(s, 2H), 3.54-3.48 (m, 4H), 3.47-3.38 (m, 4H), 2.65 (s, 4H), 1.48 (s,9H).

Step B: tert-butyl4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate.To a solution of tert-butyl4-(7-benzyl-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(7.0 g, 15.4 mmol, 1.0 eq) and DIEA (5.96 g, 46.1 mmol, 8.03 mL, 3.0 eq)in DCE (100 mL) was added 1-chloroethyl carbonochloridate (5.49 g, 38.4mmol, 2.5 eq) at 0° C. The mixture was stirred at 15° C. for 2 hours.Then the mixture was concentrated. The residue was dissolved with MeOH(100 mL) and heated to 70° C., the reaction mixture was stirred at 70°C. for 1 hour. After completion, the mixture was concentrated undervacuum. The obtained product was purified by reversed phase flash column(C18, 0.1% FA in water, 0-50% MeCN) to give tert-butyl4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(4.6 g, 12.6 mmol, 82% yield) as a yellow solid. LCMS [ESI, M+1]: 366.

Step C: To a solution of tert-butyl4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(3.60 g, 9.85 mmol, 1.0 eq), (3-methoxy-1-naphthyl)trifluoromethanesulfonate (Intermediate 30, 7.54 g, 24.6 mmol, 2.50 eq),RuPhos (919 mg, 1.97 mmol, 0.20 eq) and Cs₂CO₃ (9.63 g, 29.6 mmol, 3.0eq) in toluene (30.0 mL) was added Pd₂(dba)₃ (1.35 g, 1.48 mmol, 0.15eq). The mixture was degassed under vacuum and purged with N₂ 3 times.Then the mixture was stirred at 90° C. for 8 hours. After completion,the mixture was added water (50.0 mL) and extracted with EA (50.0 mL×3).The organic layer was dried over Na₂SO₄, filtered and concentrated. Theobtained product was purified by column chromatography (SiO₂,PE:EA=20:1-EA:MeOH=10:1) to give tert-butyl4-[7-(3-methoxy-1-naphthyl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(4.60 g, 8.82 mmol, 89% yield) as yellow solid. LCMS [ESI, M+1]: 522.

Step D: tert-butyl4-[7-(3-methoxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of tert-butyl4-[7-(3-methoxy-1-naphthyl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(3.80 g, 7.28 mmol, 1.0 eq) in EA (40.0 mL) was added m-CPBA (1.41 g,6.56 mmol, 0.90 eq) at 0° C. The mixture was stirred at 0° C. for 0.5hour. After completion, the mixture was quenched with saturated NaHSO₃aqueous (30.0 mL) and extracted with EA (50.0 mL×3). The organic layerwas dried over Na₂SO₄, filtered and concentrated. The obtained productwas purified by reversed phase flash column (C18, 0.1% FA in water,0-60% MeCN) to give tert-butyl4-[7-(3-methoxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(2.70 g, 5.02 mmol, 69% yield) as yellow solid.

¹H NMR (400 MHz, Chloroform-d) δ 8.07 (d, J=8.4 Hz, 1H), 7.76 (d, J=8.0Hz, 1H), 7.52-7.42 (m, 1H), 7.39-7.33 (m, 1H), 6.92 (d, J=2.0 Hz, 1H),6.81 (d, J=2.0 Hz, 1H), 4.42 (br s, 2H), 3.93 (s, 3H), 3.61 (br d, J=4.0Hz, 8H), 3.52-3.34 (m, 2H), 3.08-2.81 (m, 5H), 1.50 (s, 9H).

Step E: tert-butyl4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(3-methoxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of tert-butyl4-[7-(3-methoxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(800 mg, 1.49 mmol, 1.0 eq) and t-BuONa (286 mg, 2.98 mmol, 2.0 eq) intoluene (8.0 mL) was added[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methanol (396 mg, 2.98 mmol,2.0 eq). The mixture was stirred at 0° C. for 2 hours. After completion,the mixture was added water (10.0 mL) and extracted with EA (10.0 mL×3).The organic layer was dried over Na₂SO₄, filtered and concentrated. Theobtained product was purified by reversed phase flash column (C18, 0.1%FA in water, 0-60% MeCN) to give tert-butyl4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(3-methoxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(670 mg, 1.10 mmol, 74% yield) as yellow solid.

¹H NMR (400 MHz, Chloroform-d) δ=8.09 (d, J=8.4 Hz, 1H), 7.75 (d, J=8.0Hz, 1), 7.48-7.41 (m, 1H), 7.38-7.31 (m, 1H), 6.90 (d, J=2.0 Hz, 1H),6.81 (d, J=2.4 Hz, 1H), 5.29-5.06 (m, 1H), 4.44 (dd, J=4.4, 10.8 Hz,1H), 4.27-4.20 (m, 3H), 3.92 (s, 3H), 3.66-3.43 (m, 9H), 3.36 (br s,2H), 3.11-2.99 (m, 1H), 2.85 (br s, 2H), 2.70-2.55 (m, 1H), 2.52 (s,3H), 2.40-2.26 (m, 1H), 2.05-1.91 (m, 1H), 1.50 (s, 9H).

Step F:2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(3-methoxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine.To a solution of tert-butyl4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(3-methoxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(650 mg, 1.07 mmol, 1.0 eq) in DCM (1.50 mL) was added TFA (2.39 g, 21.0mmol, 1.55 mL, 19.6 eq). The mixture was stirred at 25° C. for 0.5 hour.After completion, the mixture was concentrated under vacuum. The product2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(3-methoxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(780 mg, crude, 2 TFA) as yellow oil. LCMS [ESI, M+1]: 507.

Step G:1-[4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(3-methoxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one.To a solution of2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(3-methoxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(780 mg, 1.06 mmol, 1.0 eq, 2 TFA) and DIEA (1.65 g, 12.7 mmol, 2.22 mL,12.0 eq) in DCM (8.0 mL) was added prop-2-enoyl prop-2-enoate (201 mg,1.59 mmol, 1.50 eq) at −50° C. The mixture was stirred at −50° C. for0.5 hour. After completion, the mixture was quenched with MeOH (1 mL),then concentrated under vacuum. The obtained product was purified byprep-HPLC (column: Gemini 150*25 5 u; mobile phase: [water (0.05%ammonia hydroxide v/v)-ACN]; B %: 46%-76%, 12 min) to give titlecompound1-[4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(3-methoxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(EXAMPLE 355, 300 mg, 528 umol, two steps 49% yield, 98% purity) aswhite solid. LCMS [ESI, M+1]: 561.

¹H NMR (400 MHz, Chloroform-d) δ=8.10 (d, J=8.4 Hz, 1H), 7.75 (d, J=8.0Hz, 1H), 7.49-7.42 (m, 1H), 7.40-7.32 (m, 1H), 6.91 (d, J=2.4 Hz, 1H),6.81 (d, J=2.4 Hz, 1H), 6.61 (dd, J=10.8, 16.8 Hz, 1H), 6.36 (dd, J=2.0,16.8 Hz, 1H), 5.77 (dd, J=1.6, 10.4 Hz, 1H), 5.28-5.07 (m, 1H), 4.44(dd, J=4.8, 11.2 Hz, 1H), 4.30-4.19 (m, 3H), 3.93 (s, 3H), 3.84 (br s,2H), 3.72 (br s, 2H), 3.65-3.50 (m, 5H), 3.37 (br s, 2H), 3.10-3.01 (m,1H), 2.87 (br s, 2H), 2.70-2.55 (m, 1H), 2.52 (s, 3H), 2.42-2.26 (m,1H), 2.07-1.90 (m, 1H).

Example 356

1-[4-[2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(3-methoxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: [(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methanol. To asolution of O1-tert-butyl O2-methyl(2S,4R)-4-methoxypyrrolidine-1,2-dicarboxylate (1.8 g, 6.94 mmol, 1.0eq) in THF (30.0 mL) was added LiAlH₄ (790 mg, 20.8 mmol, 3.0 eq). Themixture was stirred at −40° C. for 1 hour. Then the mixture stirred 80°C. for 2 hours under N₂ atmosphere. The reaction mixture was quenchedwith saturated Na₂SO₄ aqueous solution (6.0 mL). Then the mixture wasfiltered and the filter was concentrated. Compound[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methanol (1.1 g, 6.82 mmol,98% yield, 90% purity) was obtained as a colorless oil and used to nextstep without further purification.

¹H NMR (400 MHz, Chloroform-d) δ 3.90-3.82 (m, 1H), 3.66 (dd, J=3.2 Hz,10.8 Hz, 1H), 3.46-3.37 (m, 2H), 3.28 (s, 3H), 2.77-2.65 (m, 1H),2.64-2.57 (m, 1H), 2.35-2.30 (m, 4H), 2.11-2.01 (m, 1H), 1.90-1.79 (m,1H).

Step B: tert-butyl4-[2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(3-methoxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.A mixture of tert-butyl4-[7-(3-methoxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(800 mg, 1.49 mmol, 1.0 eq),[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methanol (454 mg, 3.12 mmol,2.1 eq), t-BuONa (296 mg, 2.98 mmol, 2.0 eq) in toluene (5.0 mL) wasdegassed and purged with N₂ for 3 times, and then the mixture wasstirred at 0° C. for 30 mins under N₂ atmosphere. After completion, thereaction mixture was added water (15.0 mL), extracted with ethyl acetate(3×20.0 mL). Combine extracts were washed with brine (50.0 mL), driedwith Na₂SO₄, the solvent was then removed under vacuum. The residue waspurified by reversed phase flash HPLC [C18, 0.1% FA in water, 0-60%MeCN]. The obtained product was adjusted with saturated NaHCO₃ aqueousto pH˜8, then concentrated, the aqueous was extracted with EA (3×50.0mL), the combined organic layer was dried over Na₂SO₄, filtered andconcentrated. Compound tert-butyl4-[2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(3-methoxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 808 umol, 54% yield, 100% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 619.

Step C:2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(3-methoxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine.To a solution of tert-butyl4-[2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(3-methoxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(450 mg, 727 umol, 1.0 eq) in DCM (6.0 mL) was added TFA (6.93 g, 60.8mmol, 4.50 mL, 83.6 eq). The mixture was stirred at 25° C. for 30 mins.After completion, the organic solvent was removed under vacuum to give2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(3-methoxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(540 mg, crude, 2TFA) as yellow oil. The crude product was used into thenext step without further purification. LCMS [ESI, M+1]: 519.

Step D: 1-[4-[2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(3-methoxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one.To a solution of2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(3-methoxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(540 mg, 2TFA) in DCM (6.0 mL) was dropwise added prop-2-enoylprop-2-enoate (130 mg, 1.03 mmol) and DIEA (800 mg, 6.19 mmol, 1.08 mL)under N₂ atmosphere. The mixture was stirred at 0° C. for 30 min. Aftercompletion, the reaction was quenched with methanol (10.0 mL) and themixture was removed under vacuum. The residue was purified by prep-HPLC(column: Phenomenex Gemini 150*25 mm*10 um; mobile phase: [water (0.05%ammonia hydroxide v/v)-ACN]; B %: 48%-78%, 12 min) and underlyophilization. Title compound1-[4-[2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(3-methoxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(EXAMPLE 356, 112 mg, 196 umol, 99% purity, 18% yield) was obtained aswhite solid. LCMS [ESI, M+1]: 573.

¹H NMR (400 MHz, Chloroform-d) δ 8.09 (d, J=8.4 Hz, 1H), 7.75 (d, J=8.0Hz, 1H), 7.48-7.44 (m, 1H), 7.38-7.34 (m, 1H), 6.91 (d, J=2.4 Hz, 1H),6.81 (d, J=2.4 Hz, 1H), 6.61 (dd, J=10.4 Hz, 16.8 Hz, 1H), 6.35 (dd,J=2.0 Hz, 16.8 Hz, 1H), 5.76 (dd, J=1.6 Hz, 9.6 Hz, 1H), 4.41 (dd, J=4.8Hz, 10.8 Hz, 1H), 4.24 (s, 2H), 4.22-4.16 (m, 1H, 4.00-3.94 (m, 1H),3.92 (s, 3H), 3.83-3.67 (m, 4H), 3.62-3.48 (m, 4H), 3.47-3.42 (m, 1H),3.40-3.33 (m, 2H), 3.30 (s, 3H), 2.94-2.82 (m, 3H), 2.47 (s, 3H), 2.33(dd, J=6.0 Hz, 10.0 Hz, 1H), 2.12-2.04 (m, 1H), 2.01-1.93 (m, 1H).

Example 357

1-[4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: tert-butyl4-[7-benzyl-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of [(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methanol(631 mg, 4.74 mmol, 3.76 eq) in THF (7.0 mL) was added NaH (126 mg, 3.16mmol, 60% purity, 2.51 eq) at 0° C. Then the mixture was stirred at 0°C. for 0.5 hr. Then tert-butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(700 mg, 1.26 mmol, 1.0 eq) was added to the above mixture. Afteraddition, the mixture was stirred at 70° C. for 12 hrs. Aftercompletion, the mixture was quenched with saturated NH₄Cl aqueous (15.0mL) and extracted with EA (3×20.0 mL). The organic layer was dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (SiO₂,Dichloromethane:Methanol=20:1 to 10:1) to give tert-butyl4-[7-benzyl-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(530 mg, 980 umol, 78% yield) as yellow oil. LCMS [ESI, M+1]: 541.

¹H NMR (400 MHz, Chloroform-d) δ 7.24-7.13 (m, 5H), 5.08-4.91 (m, 1H),4.23 (dd, J=4.4 Hz, 10.8 Hz, 1H), 4.04 (dd, J=6.0 Hz, 10.8 Hz, 1H), 3.53(s, 2H), 3.45-3.42 (m, 2H), 3.38-3.33 (m, 5H), 3.31-3.27 (m, 4H),2.90-2.84 (m, 1H), 2.52-2.46 (m, 3H), 2.35 (s, 3H), 2.21-2.09 (m, 1H),1.87-1.73 (m, 3H), 1.34 (s, 9H).

Step B: tert-butyl4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of tert-butyl4-[7-benzyl-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(480 mg, 887 umol, 1 eq) in MeOH (6.0 mL) was added Pd(OH)₂/C (270 mg,10% purity) under N₂. The suspension was degassed under vacuum andpurged with H₂ several times. The mixture was stirred under H₂ (15 Psi)at 20° C. for 2 hours. After completion, the mixture was filtered andconcentrated. The residue was purified by column chromatography (SiO₂,EA/MeOH=20:1 to 10:1). The product tert-butyl4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(350 mg, 706 umol, 79% yield, 91% purity) was obtained as yellow oil.LCMS [ESI, M+1]: 451.

Step C: To a mixture of tert-butyl4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(280 mg, 621 umol, 1.0 eq), Pd₂(dba)₃ (85.3 mg, 93.2 umol, 0.15 eq),RuPhos (58.0 mg, 124.3 umol, 0.2 eq) and Cs₂CO₃ (404 mg, 1.24 mmol, 2.0eq) in toluene (10.0 mL) was added (4-bromo-2-naphthyl)2,2-dimethylpropanoate (Intermediate 54, 572 mg, 1.86 mmol, 3.0 eq). Themixture was stirred at 110° C. for 5 hrs under N₂. The mixture wasquenched with water (15.0 mL) and extracted with EA (3×20.0 mL). Theorganic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by reversedphase flash HPLC (¹⁸C, 0.1% FA in water, 0-70% MeCN). The obtainedproduct was adjusted with saturated NaHCO₃ aqueous to pH˜8, thenconcentrated, the aqueous was extracted with EA (3×40.0 mL), thecombined organic layer was dried over Na₂SO₄, filtered and concentrated.Compound tert-butyl4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(190 mg, 272 umol, 44% yield, 97% purity) was obtained as a yellow oil.LCMS [ESI, M+1]: 677.

Step D:[4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]-2,2-dimethylpropanoate.To a mixture of tert-butyl4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(110 mg, 162 umol, 1.0 eq) in DCM (1.5 mL) was added TFA (2.31 g, 20.2mmol, 1.5 mL, 124 eq) in portions at 25° C. under N₂. The mixture wasstirred at 25° C. for 1 hr. After completion, the reaction mixture wasconcentrated to give[4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]-2,2-dimethylpropanoate(200 mg, crude, 2TFA) as yellow solid, which was used into the next stepwithout further purification. LCMS [ESI, M+1]: 577.

Step E:[4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-4-(4-prop-2-enoylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]-2,2-dimethylpropanoate.To a mixture of[4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]-2,2-dimethylpropanoate(200 mg, 2TFA) and TEA (493 mg, 4.87 mmol, 678 uL) in DCM (2.0 mL) wasadded prop-2-enoyl prop-2-enoate (40.9 mg, 324 umol) in portions at 0°C. under N₂. The mixture was stirred at 0° C. for 1 hr. Aftercompletion, the reaction mixture was quenched by MeOH (3.0 mL) at 0° C.,and then concentrated under reduced pressure to give a residue. Theresidue was purified by column chromatography (SiO₂, EA/MeOH 20:1 to10:1). Compound[4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-4-(4-prop-2-enoylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]-2,2-dimethylpropanoate(100 mg, 153 umol, 97% purity) was obtained as a yellow oil. LCMS [ESI,M+1]: 631.

Step F:1-[4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one.A mixture of[4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-4-(4-prop-2-enoylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]-2,2-dimethylpropanoate(39.0 mg, 61.8 umol, 1.0 eq) and NaOH (61.8 mg, 1.55 mmol, 25.0 eq) inTHF (1.5 mL) and H₂O (1.5 mL) was stirred at 25° C. for 14 hours. Aftercompletion, the reaction mixture was quenched by water (10.0 mL) andthen extracted with EA (3×15.0 mL). The organic layer was dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by prep-HPLC (column: PhenomenexGemini 150*25 mm*10 um; mobile phase: [water (0.05% ammonia hydroxidev/v)-ACN], B: 38%-68%, 12 min) and lyophilization. Title compound1-[4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(EXAMPLE 357, 10.1 mg, 18.4 umol, 30% yield, 99% purity) was obtained asa yellow solid. LCMS [ESI, M+1]: 547.

SFC Conditions: 100% ee.

¹H NMR (400 MHz, Chloroform-d) δ 8.04 (d, J=8.4 Hz, 1H), 7.65 (d, J=8.4Hz, 1H), 742 (t, J=72 Hz, 1H), 7.30-7.34 (m, 1H), 6.88 (d, J=1.6 Hz,1H), 6.72 (d, J=2.0 Hz, 1H), 6.60 (dd, J=10.4 Hz, 16.81 Hz, 1H), 6.37(dd, J=1.61 Hz, 16.8 Hz, 1H), 5.79 (dd, J=2.0 Hz, 10.2 Hz, 1H),5.28-5.14 (m, 1H), 4.46 (dd, J=4.8 Hz, 11.2 Hz, 1H), 4.32 (dd, J=5.2 Hz,11.2 Hz, 1H), 4.18 (s, 2H), 3.82-3.68 (m, 2H), 3.66-3.55 (m, 4H),3.52-3.42 (m, 4H), 3.35-3.21 (m, 2H), 3.17-3.10 (m, 1H), 2.82-2.68 (m,2H), 2.63-2.74 (m, 1H), 2.61 (s, 3H), 2.40-2.25 (m, 1H), 2.13-1.94 (m,1H).

Example 358

1-[(2S)-4-[2-[[(2-S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-prop-2-ynyl-piperazin-1-yl]prop-2-en-1-one

Step A: (2S)-2-(tert-butoxycarbonylamino)pent-4-ynoic acid. To asuspension of (2S)-2-aminopent-4-ynoic acid (5 g, 44.2 mmol, 1 eq) inTHF (15 mL) was added H₂O (15 mL), K₂CO₃ (18.3 g, 133 mmol, 3 eq) andBoc₂O (11.1 g, 50.8 mmol, 11.7 mL, 1.15 eq). Additional water was addedto produce a solution which was stirred for 12 hours at 25 TC. Theorganic solvent was then evaporated and the aqueous solution was washedwith t-butyl methyl ether, then acidified to pH=3 with 1N HCl acid. Thesolution was extracted with ethyl acetate (2×100 mL). The solvent wasevaporated to give (2S)-2-(tert-butoxycarbonylamino)pent-4-ynoic acid (8g, 37.5 mmol, 85% yield) as a colorless oil used without furtherpurification. LCMS [ESI, M+1]: 589).

¹H NMR (400 MHz, chloroform-d) δ 7.76 (br d, J=8.4 Hz, 1H), 7.62 (t,J=17.6 Hz, 1H), 7.53 (d, J=7.2 Hz, 1H), 7.45 (td, J=8.0, 13.2 Hz, 1H),7.34 (t, J=7.6 Hz, 1H), 7.26-7.18 (m, 1H), 5.10 (br s, 1H), 4.49-4.33(m, 2H), 4.21-4.01 (m, 3H), 3.96-3.79 (m, 2H), 3.60 (br d, J=6.8 Hz,1H), 3.44 (br d, J=13.61 Hz, 1H), 3.32-2.97 (m, 5H), 2.88-2.53 (m, 4H),2.48 (d, J=2.8 Hz, 3H), 2.29 (br d, J=8.8 Hz, 1H), 2.11-2.00 (m, 1H),1.87-1.71 (m, 3H).

Step B: ethyl2-[benzyl-[(2S)-2-(tert-butoxycarbonylamino)pent-4-ynoyl]amino]acetate.To a solution of (2S)-2-(tert-butoxycarbonylamino)pent-4-ynoic acid(7.75 g, 36.4 mmol, 1 eq), ethyl 2-(benzylamino)acetate (7.02 g, 36.4mmol, 1 eq) and HATU (16.6 g, 43.5 mmol, 1.20 eq) in DMF (50 mL) wasadded TEA (7.35 g, 72.7 mmol, 10.1 mL, 2.00 eq) at 25° C. The mixturewas stirred at 25° C. for 0.5 h. The mixture was diluted with ethylacetate (150 mL) and washed with water (3×200 mL) and brine (1×100 mL).The separated organic layer was washed with water (1×100 mL) and brine(1×100 mL), dried over sodium sulfate, filtered and concentrated undervacuum. The residue was used to next step without further purification.Compound ethyl2-[benzyl-[(2S)-2-(tert-butoxycarbonylamino)pent-4-ynoyl]amino]acetate(13.7 g, 32.1 mmol, 88.3% yield, 91% purity) was obtained as red oilwhich become to red solid as standing at 25° C. for 16 hours. LCMS [ESI,M−99]: 289.

Step C: (3S)-1-benzyl-3-prop-2-ynyl-piperazine-2,5-dione. To a solutionof ethyl 2-[benzyl-[(2S)-2-(tert-butoxycarbonylamino)pent-4-ynoyl]amino]acetate (11.7 g, 30.1 mmol, 1 eq) in DCM (40 mL) wasadded TFA (46.2 g, 405 mmol, 30 mL, 13.5 eq) at 0° C. and the mixturewas stirred at 25° C. for 0.5 hour. The mixture was concentrated undervacuum and toluene (30 mL) was added. After stirred at 100° C. for 1hour, the mixture was concentrated under vacuum. The residue wasdissolved into ethyl acetate (200 mL) and basified with saturatedaqueous sodium carbonate solution to pH=8. The separated organic layerwas washed with water (1×200 mL) and brine (1×100 mL), dried over sodiumsulfate, filtered and concentrated under vacuum. The residue wastriturated with (ethyl acetate/petroleum ether 1/5, 100 mL) and theprecipitate was filtered. The filter cake was dried under vacuum.Compound (3S)-1-benzyl-3-prop-2-ynyl-piperazine-2,5-dione (5 g, 20.5mmol, 68% yield, 99.5% purity) was obtained as a white solid. LCMS [ESI,M+1]: 243.

¹H NMR (400 MHz, chloroform-d) δ=7.46-7.20 (m, 5H), 6.59 (br s, 1H),4.76 (d, J=14.4 Hz, 1H), 4.50 (d, J=14.4 Hz, 1H), 4.20 (br d, J=4.4 Hz,1H), 4.04-3.90 (m, 1H), 3.89-3.76 (m, 1H), 2.95-2.69 (m, 2H), 2.05 (t,J=2.8 Hz, 1H).

Step D: (3S)-1-benzyl-3-prop-2-ynyl-piperazine. To a mixture of(3S)-1-benzyl-3-prop-2-ynyl-piperazine-2,5-dione (5.00 g, 20.6 mmol,1.00 eq) in THF (50.0 mL) was added LiAlH₄ (3.13 g, 82.6 mmol, 4.00 eq)at 25° C. After stirred at 65° C. for 12 hours, the mixture was filteredoff and the filter cake was washed with ethyl acetate (100 mL). Thefiltrate was concentrated under vacuum to give(3S)-1-benzyl-3-prop-2-ynyl-piperazine (4.10 g, 19.1 mmol, 93% yield) asa yellow oil and used into next step without further purification.

¹H NMR (400 MHz, chloroform-d) δ=7.37-7.24 (m, 5H), 3.55-3.47 (m, 2H),3.03-2.86 (m, 3H), 2.85-2.78 (m, 1H), 2.73 (br d, J=11.2 Hz, 1H),2.33-2.20 (m, 2H), 2.13-2.04 (m, 1H), 2.02 (t, J=2.8 Hz, 1H), 1.90-1.83(m, 1H).

Step E: tert-butyl (2S)-4-benzyl-2-prop-2-ynyl-piperazine-1-carboxylate.A mixture of (3S)-1-benzyl-3-prop-2-ynyl-piperazine (2.00 g, 9.33 mmol,1.00 eq), TEA (2.83 g, 28.0 mmol, 3.90 mL, 3.00 eq) and (Boc)₂O (10.2 g,46.7 mmol, 10.7 mL, 5.00 eq) in THF (20.0 mL) was stirred at 25° C. for1 hour. The mixture was diluted with water (1×20.0 mL), extracted withethyl acetate (3×20.0 mL). The combine organic layer was wash with brine(1×30.0 mL), dried over Na₂SO₄, filtered and concentrated under vacuum.The residue was purified by column chromatography (SiO₂, petroleumether/ethyl acetate 5/1). The desired fractions were collected andconcentrated under vacuum to give tert-butyl(2S)-4-benzyl-2-prop-2-ynyl-piperazine-1-carboxylate (1.50 g, 4.20 mmol,45% yield, 88% purity) as a colorless oil. LCMS [ESI, M+1]: 315.

¹H NMR (400 MHz, chloroform-d) δ=7.38-7.27 (m, 5H), 4.26 (br s, 1H),3.99-3.74 (m, 1H), 3.59-3.45 (m, 2H), 3.08-2.89 (m, 2H), 2.79-2.68 (m,2H), 2.62-2.53 (m, 1H), 2.11 (dd, J=3.6, 11.2 Hz, 1H), 2.06-1.98 (m,1H), 1.89 (t, J=2.8 Hz, 1H), 1.48-1.45 (m, 9H).

Step F: (2S)-2-prop-2-ynylpiperazine. A mixture of tert-butyl(2S)-4-benzyl-2-prop-2-ynyl-piperazine-1-carboxylate (1.40 g, 4.45 mmol,1.00 eq), 1-chloro-1-(1-chlorovinyloxy)ethane (2.51 g, 17.8 mmol, 4.00eq) in DCE (20.0 mL) was stirred at 85° C. for 1 hour. The mixture wasconcentrated under vacuum. The residue was dissolved in methanol (20.0mL) and stirred at 65° C. for 1 hour. The mixture was concentrated undervacuum and triturated with petroleum ether (10.0 mL) to give(2S)-2-prop-2-ynylpiperazine (0.80 g, crude, 2 HCl) as a yellow solidand used into next step without further purification.

¹H NMR (400 MHz, methanol-d4) δ=4.56-4.44 (m, 1H), 3.88-3.80 (m, 1H),3.79-3.73 (m, 1H), 3.62-3.34 (m, 4H), 2.87-2.76 (m, 3H).

Step G:4-benzyloxy-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine.A mixture of4-benzyloxy-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine(2.00 g, 5.64 mmol, 1.00 eq), 1-bromonaphthalene (1.75 g, 8.46 mmol,1.18 mL, 1.50 eq), Pd₂(dba)₃ (517 mg, 564 umol, 0.10 eq), RuPhos (527mg, 1.13 mmol, 0.20 eq) and Cs₂CO₃ (3.68 g, 11.3 mmol, 2.00 eq) intoluene (20.0 mL) was stirred at 110° C. for 3 hours under N₂. Themixture was diluted with water (5.00 mL), extracted with ethyl acetate(3×5.00 mL). The organic layers were washed with brine (1×10.0 mL),dried over Na₂SO₄, filtered and concentrated under vacuum. The residuewas purified by reversed phase flash [water (TFA, 0.10%)/acetonitrile].The desired fraction was collected and adjusted pH>7 by saturated sodiumbicarbonate (5.00 mL), and then extracted with ethyl acetate (3×20.0mL). The combined organic layers were washed with brine (1×30.0 mL),dried over Na₂SO₄, filtered and concentrated under vacuum to give4-benzyloxy-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(1.34 g, 2.78 mmol, 49% yield, 99.6% purity) as a yellow solid. LCMS[ESI, M+1]: 481.

¹H NMR (400 MHz, chloroform-d) δ=8.22-8.16 (m, 1H), 7.89-7.82 (m, 1H),7.59 (d, J=8.0 Hz, 1H), 7.51-7.45 (m, 4H), 7.45-7.33 (m, 4H), 7.14 (dd,J=0.8, 7.2 Hz, 1H), 5.49 (s, 2H), 4.45 (dd, J=5.6, 10.4 Hz, 1H),4.27-4.18 (m, 3H), 3.55-3.24 (m, 2H), 3.12 (br t, J=7.6 Hz, 1H), 2.89(br s, 2H), 2.76-2.65 (m, 1H), 2.50 (s, 3H), 2.35-2.24 (m, 1H),2.14-2.06 (m, 1H), 1.91-1.78 (m, 3H).

Step H:2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-ol.A mixture of4-benzyloxy-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(1.30 g, 2.70 mmol, 1.00 eq) and Pd/C (0.20 g, 10% purity) in methanol(200 mL) was stirred at 25° C. for 1 hour under H₂ at 15 psi. Thecatalyst was filtered off and the filtrate was concentrated under vacuumto give2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-ol(1.00 g, 1.90 mmol, 70% yield, 74% purity) as a yellow solid and usedinto next step without further purification. LCMS [ESI, M+1]: 391.

¹H NMR (400 MHz, chloroform-d) δ=8.24-8.16 (m, 1H), 7.90-7.81 (m, 1H),7.59 (d, J=8.4 Hz, 1H), 7.54-7.47 (m, 2H), 7.42 (t, J=7.6 Hz, 1H), 7.14(d, J=7.6 Hz, 1H), 4.43-4.31 (m, 2H), 4.05 (s, 2H), 3.38 (br s, 2H),3.18-3.10 (m, 1H), 2.79 (br s, 2H), 2.70-2.54 (m, 2H), 2.47 (s, 3H),2.32 (dt, J=7.2, 9.6 Hz, 1H), 2.02-1.96 (m, 1H), 1.91-1.75 (m, 3H).

Step I:[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]trifluoromethanesulfonate. To a solution of2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-ol(0.40 g, 1.02 mmol, 1.00 eq) and TEA (207 mg, 2.05 mmol, 285 uL, 2.00eq) in dichloromethane (10.0 mL) was added Tf₂O (318 mg, 1.13 mmol, 186uL, 1.10 eq) at −40° C. After stirred −40° C. for 0.25 hour, the mixturewas diluted with water (3.00 mL) and then extracted with ethyl acetate(3×5.00 mL). The extracts were washed with brine (1×5.00 mL), dried overNa₂SO₄, filtered and concentrated under vacuum. The residue was purifiedby column chromatography (SiO₂, ethyl acetate/methanol=10/1). Thedesired fractions were collected and concentrated under vacuum to give[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]trifluoromethanesulfonate (0.40 g, 528 umol, 52% yield, 69% purity) as ayellow solid. LCMS [ESI, M+1]: 523.

Step J:2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-4-[(3S)-3-prop-2-ynylpiperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine.A mixture of[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]trifluoromethanesulfonate(0.38 g, 727 umol, 1.00 eq), (2S)-2-prop-2-ynylpiperazine (350 mg,crude, 2 HCl) and DIEA (939 mg, 7.27 mmol, 1.27 mL, 10.0 eq) in DMF(4.00 mL) was stirred at 100° C. for 0.25 hour. The mixture was dilutedwith water (5.00 mL) and extracted with ethyl acetate (3×10.0 mL). Theextracts were washed with brine (1×10.0 mL), dried over Na₂SO₄, filteredand concentrated under vacuum. The residue was purified by reversedphase flash [water (FA, 0.1%)/acetonitrile] The desired fractions werecollected and lyophilized to give2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-4-[(3S)-3-prop-2-ynylpiperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(0.20 g, 336 umol, 46% yield, 99% purity, 2 FA) as a yellow oil. LCMS[ESI, M+1]: 497.

Step K:1-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-prop-2-ynyl-piperazin-1-yl]prop-2-en-1-one.To a solution of2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-4-[(3S)-3-prop-2-ynylpiperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(145 mg, 246 umol, 1.00 eq, 2 FA) and TEA (374 mg, 3.69 mmol, 514 uL,15.0 eq) in dichloromethane (4.00 mL) was added prop-2-enoyl chloride(22.3 mg, 246 umol, 20.1 uL, 1.00 eq) at −40° C. After stirred at 25° C.for 0.25 h, the mixture was diluted with water (3.00 mL), and thenextracted with dichloromethane (3×3.00 mL). The extracts were dried overNa₂SO₄, filtered and concentrated under vacuum. The residue was purifiedby prep-HPLC (column: Phenomenex Gemini 150*25 mm*10 um, mobile phase:[water (10 mM NH₄HCO₃)-ACN]; B %: 57%-87%, 12 min). The desiredfractions were collected and lyophilized to give title compound1-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-prop-2-ynyl-piperazin-1-yl]prop-2-en-1-one(EXAMPLE 358, 25.6 mg, 46.3 umol, 19% yield, 99.5% purity) as a brownsolid. LCMS [ESI, M+1]: 551.

SFC conditions: “OD-3S_3_40_3 ML Column: Chiralcel OD-3 100×4.6 mm I.D.,3 um, Mobile phase: 40% methanol (0.05% DEA) in CO₂, Flow rate: 3mL/min, Wavelength: 220 nm”.

¹H NMR (400 MHz, chloroform-d) δ=8.21 (m, 1H), 7.91-7.81 (m, 1H), 7.60(br d, J=8.0 Hz, 1H), 7.54-7.47 (m, 2H), 7.46-7.39 (m, 1H), 7.14 (d,J=7.2 Hz, 1H), 6.65 (br s, 1H), 6.36 (br d, J=16.8 Hz, 1H), 5.77 (dd,J=2.0, 10.8 Hz, 1H), 5.00-4.52 (m, 1H), 4.46-4.36 (m, 1H), 4.34-3.81 (m,6H), 3.47 (m, 1H), 3.38-3.21 (m, 2H), 3.19-2.90 (m, 4H), 2.84 (br s,1H), 2.73-2.52 (m, 3H), 2.48 (s, 3H), 2.34-2.24 (m, 1H), 2.10-2.03 (m,1H), 1.90-1.70 (m, 4H).

Example 359

2-((S)-1-acryloyl-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: tert-Butyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.A mixture of 1-bromo-8-methyl-naphthalene (Intermediate 69, 507 mg, 1.65mmol, 1.3 eq), tert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(Intermediate 66, 600 mg, 1.27 mmol, 1 eq), Cs₂CO₃ (1.04 g, 3.18 mmol,2.5 eq), RuPhos (118 mg, 254 umol, 0.2 eq) and Pd₂(dba)₃ (233 mg, 254umol, 0.2 eq) in toluene (10 mL) was degassed and purged with N₂ for 3times, and then the mixture was stirred at 100° C. for 2 hours under N₂atmosphere. The reaction mixture was diluted with water (30 mL) andextracted with ethyl acetate (20 mL×3). The combined organic layers werewashed with brine (20 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give a residue. The residue was purified byreversed phase flash [water (0.1% formic acid)/acetonitrile)]. Themixture was adjusted pH˜7 with saturated NaHCO₃ aqueous solution andextracted with ethyl acetate (20 mL×3). The combined organic layers werewashed with brine (20 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give the product. Compound tert-Butyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(310 mg, 501 umol, 39% yield, 99% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 612.

¹HNMR (400 MHz, chloroform-d) δ=7.74-7.60 (m, 2H), 7.46-7.37 (m, 1H),7.34 (t, J=7.6 Hz, 1H), 7.27-7.16 (m, 2H), 4.61 (br s, 1H), 4.43-4.33(m, 1H), 4.30-4.14 (m, 2H), 4.10-3.72 (m, 4H), 3.60-3.44 (m, 1H), 3.38(br dd, J=3.6, 13.6 Hz, 1H), 3.24-3.04 (m, 4H), 3.03-2.84 (m, 5H),2.82-2.53 (m, 4H), 2.52-2.42 (m, 3H), 2.29 (br s, 1H), 2.05-1.95 (m,1H), 1.91-1.69 (m, 2H), 1.52 (s, 9H).

Step B:2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(310 mg, 506 umol, 1 eq) in DCM (500 uL) was added TFA (866 mg, 7.60mmol, 562 uL, 15 eq). The mixture was stirred at 25° C. for 1 hour. Thereaction mixture was concentrated under vacuum. Compound2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(317 mg, 506 umol, 99% yield, TFA) was obtained as a yellow oil and usedto next step directly without purification. LCMS [ESI, M+1]: 512.

Step C:2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-methyl-1-napthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(317 mg, 506 umol, 1 eq, TFA) in DCM (5 mL) was added TEA (512 mg, 5.07mmol, 705 uL, 10 eq) at 0° C. After addition, and prop-2-enoylprop-2-enoate (51.1 mg, 405 umol, 0.8 eq) in DCM (1 mL) was addeddropwise at 0° C. The resulting mixture was stirred at 25° C. for 1hour. The reaction mixture was quenched with saturated NaHCO₃ aqueoussolution (1 mL) and extracted with ethyl acetate (20 mL×3). The combinedorganic layers were washed with brine (20 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by prep-HPLC (column: Phenomenex Gemini 150*25mm*10 um, mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %:50%-80%, 12 min). Title compound2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 359, 60.2 mg, 105 umol, 21% yield, 99.5% purity) was obtainedas a white solid. LCMS [ESI, M+1]: 566.

SFC condition: “OJ-3S_5_5_40_3 ML Column: Chiralcel OJ-3 100×4.6 mmI.D., 3 um Mobile phase: ethanol (0.05% DEA) in CO₂ from 5% to 40% Flowrate: 3 mL/min Wavelength: 220 nm”.

¹H NMR (400 MHz, chloroform-d) δ=7.75-7.60 (m, 2H), 7.46-7.38 (m, 1H),7.34 (t, J=7.6 Hz, 1H), 7.27-7.17 (m, 2H), 6.57 (s, 1H), 6.46-6.33 (m,1H), 5.83 (br d, J=10.4 Hz, 1H), 5.07 (br s, 1H), 4.64 (br s, 1H),4.44-4.32 (m, 1H), 4.31-4.21 (m, 1H), 4.20-4.03 (m, 3H), 3.98-3.83 (m,1H), 3.78-3.62 (m, 1H), 3.60-3.36 (m, 2H), 3.23-2.96 (m, 5H), 2.92 (s,3H), 2.88-2.74 (m, 1H), 2.73-2.55 (m, 2H), 2.47 (d, J=4.4 Hz, 3H),2.35-2.21 (m, 1H), 2.13-1.97 (m, 1H), 1.90-1.74 (m, 3H).

Alternatively, EXAMPLE 359 may be prepared as follows:

Step A: tert-Butyl4-[(3S)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate.To a solution of tert-butyl2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (18.8g, 61.7 mmol, 1 eq) in DMF (200 mL) was added DIEA (15.9 g, 123 mmol,21.5 mL, 2 eq) and benzyl (2S)-2-(cyanomethyl)piperazine-1-carboxylate(Intermediate 63, 16.0 g, 61.7 mmol, 1 eq). After stirred at 80° C. for1.5 hour, the reaction mixture was diluted with ethyl acetate (200 mL)and washed with water (200 mL×3). The combined organic layers werewashed with brine (200 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give a residue. The residue was purified bycolumn chromatography (SiO₂, Petroleum ether/Ethyl acetate=50/1 to 2/1).Compound tert-Butyl4-[(3S)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(26 g, 48.8 mmol, 79% yield, 99% purity) was obtained as a white solid.LCMS [ESI, M+1]: 527.

¹H NMR (400 MHz, chloroform-d) δ=7.43-7.34 (m, 5H), 5.20 (s, 2H),4.73-4.60 (m, 2H), 4.45 (d, J=19.2 Hz, 1H), 4.13-4.02 (m, 2H), 3.94-3.75(m, 2H), 3.45-3.25 (m, 3H), 3.11 (td, J=3.6, 12.4 Hz, 1H), 2.88-2.59 (m,4H), 1.60 (s, 9H).

Step B: tert-Butyl4-[(3S)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate.A mixture of [(2S)-1-methylpyrrolidin-2-yl]methanol (10.5 g, 91.1 mmol,10.8 mL, 2 eq), tert-butyl 4-[(3S)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(24 g, 45.6 mmol, 1 eq), Pd₂(dba)₃ (6.18 g, 6.84 mmol, 0.15 eq), RuPhos(4.26 g, 9.12 mmol, 0.2 eq) and Cs₂CO₃ (37.1 g, 114 mmol, 2.5 eq) intoluene (450 mL) was degassed and purged with N₂ for 3 times, and thenthe mixture was stirred at 90° C. for 5 hours under N₂ atmosphere. Thereaction mixture was diluted with water (200 mL) and extracted withethyl acetate (500 mL×3). The combined organic layers were washed withbrine (200 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by columnchromatography (Al₂O₃, ethyl acetate/methanol=1/0 to 10/1). Compoundtert-Butyl4-[(3S)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(25 g, 35.9 mmol, 79% yield, 87% purity) was obtained as a yellow solid.LCMS [ESI, M+1]: 606.

Step C: benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of tert-butyl4-[(3S)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(16 g, 26.4 mmol, 1 eq) in dioxane (100 mL) was added HCl/dioxane (4 M,99.1 mL, 15 eq). The mixture was stirred at 0° C. for 1 hour. Thedioxane was decanted and the solid was collected. The solid residue wasdiluted with water (50 mL) and dichloromethane (200 mL), then adjustedpH=8 with saturated Na₂CO₃ aqueous solution and extracted with ethylacetate (200 mL×3). The combined organic layers were washed with brine(100 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(Intermediate 65, 13.5 g, 24.5 mmol, 93% yield, 91.6% purity) as ayellow oil and used next step without purification. LCMS [ESI, M+1]:506.

¹H NMR (400 MHz, chloroform-d) δ=7.45-7.31 (m, 5H), 5.19 (s, 2H), 4.65(br s, 1H), 4.40-4.31 (m, 1H), 4.14-4.04 (m, 2H), 4.03-3.91 (m, 3H),3.91-3.77 (m, 1H), 3.24 (d, J=13.2 Hz, 2H), 3.16-3.05 (m, 2H), 3.04-2.89(m, 2H), 2.81 (br s, 1H), 2.75-2.51 (m, 4H), 2.47 (s, 3H), 2.35-2.22 (m,1H), 2.08-2.00 (m, 1H), 1.92-1.76 (m, 3H).

Step D: benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.A mixture of benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(10 g, 19.8 mmol, 1 eq), 1-bromo-8-methyl-naphthalene (Intermediate 69,5.68 g, 25.7 mmol, 1.3 eq), RuPhos (2.77 g, 5.93 mmol, 0.3 eq), Cs₂CO₃(16.1 g, 49.5 mmol, 2.5 eq) and Pd₂(dba)₃ (3.62 g, 3.96 mmol, 0.2 eq) intoluene (100 mL) was degassed and purged with N₂ for 3 times, and thenthe mixture was stirred at 90° C. for 6 hours under N₂ atmosphere. Thereaction mixture was diluted with water (100 mL) and extracted withethyl acetate (200 mL×3). The combined organic layers were washed withbrine (100 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by reversedphase flash [water (0.1% formic acid)/acetonitrile)]. The mixture wasadjusted pH=7 with saturated NaHCO₃ aqueous solution and extracted withethyl acetate (500 mL×3). The combined organic layers were washed withbrine (200 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(9 g 12.9 mmol, 33% yield, 93% purity) as a yellow solid. LCMS [ESI,M+1]: 646.

¹H NMR (400 MHz, C₂D₂Cl₄) δ=7.32 (d, J=8.0 Hz, 1H), 7.26 (t, J=8.0 Hz,1H), 7.08-6.93 (m, 7H), 6.91-6.78 (m, 2H), 4.81 (s, 2H), 4.30 (s, 1H),4.13-3.95 (m, 1H), 3.88-3.33 (m, 6H), 3.22-2.87 (m, 2H), 2.86-2.65 (m,4H), 2.65-2.42 (m, 5H), 2.41-2.32 (m, 1H), 2.30-2.13 (m, 2H), 2.07 (d,J=7.2 Hz, 3H), 1.92 (br s, 1H), 1.72-1.45 (m, 4H).

Step E: 2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(8 g, 12.4 mmol, 1 eq) in MeOH (100 mL) was added Pd/C (2 g, 10% purity)and NH₃·MeOH (50 mL, 15%) under N₂. The suspension was degassed undervacuum and purged with H₂ several times. The mixture was stirred underH₂ (15 psi) at 25° C. for 1 hour. The mixture was concentrated undervacuum. Compound 2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(5.7 g, 10.0 mmol, 81% yield, 90% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 512.

¹H NMR (400 MHz, chloroform-d) δ=7.69 (d, J=8.0 Hz, 1H), 7.64 (dd,J=3.2, 7.6 Hz, 1H), 7.40 (td, J=4.4, 7.6 Hz, 1H), 7.34 (t, J=7.6 Hz,1H), 7.26-7.19 (m, 2H), 4.46-4.34 (m, 1H), 4.25-4.03 (m, 2H), 3.97-3.69(m, 3H), 3.49-3.44 (m, 1H), 3.39-3.07 (m, 5H), 3.06-2.83 (m, 6H),2.76-2.63 (m, 1H), 2.62-2.51 (m, 3H), 2.48 (d, J=3.2 Hz, 3H), 2.35-2.22(m, 1H), 2.13-1.98 (m, 1H), 1.83-1.69 (m, 3H).

Step F:2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(6.4 g, 12.5 mmol, 1 eq) in dichloromethane (120 mL) was added TEA (19g, 187 mmol, 26 mL, 15 eq) at −40° C. After addition, a solution ofprop-2-enoyl chloride (1.70 g, 18.8 mmol, 1.53 mL, 1.5 eq) indichloromethane (2 mL) was added dropwise at −40° C. After stirred at−40° C. for 0.5 hour, the reaction mixture was quenched with saturatedNaHCO₃ aqueous solution (10 mL), then diluted with water (50 mL) andextracted with dichloromethane (50 mL×3). The combined organic layerswere washed with brine (20 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by column chromatography (SiO₂, DCM/MeOH=100/1 to 10/1) andfurther purified by prep-HPLC (column: Kromasil 250*50 mm*10 um; mobilephase: [water (0.225% FA)-ACN]; B %: 20%-50%, 28 min). The mixture wasadjusted pH=7 with saturated NaHCO₃ aqueous solution and extracted withdichloromethane (20 mL×3). The combined organic layers were washed withbrine (20 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give title compound2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 359, 2.3 g, 4.03 mmol, 32% yield, 99% purity) as a yellowsolid. LCMS [ESI, M+1]: 566.

¹H NMR (400 MHz, chloroform-d) δ=7.74-7.59 (m, 2H), 7.46-7.36 (m, 1H),7.33 (t, J=7.6 Hz, 1H), 7.26-7.15 (m, 2H), 6.70-6.47 (s, 1H), 6.39 (d,J=16.4 Hz, 1H), 5.82 (d, J=10.4 Hz, 1H), 5.16-4.47 (m, 1H), 4.44-4.32(m, 1H), 4.30-3.62 (m, 6H), 3.58-3.26 (m, 2H), 3.25-2.95 (m, 5H), 2.91(s, 3H), 2.86-2.55 (m, 4H), 2.48 (d, J=5.2 Hz, 3H), 2.36-2.21 (m, 1H),2.13-2.02 (m, 1H), 1.92-1.67 (m, 3H).

Example 360

2-[(2S)-4-[7-(8-ethyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Insert: 1-bromo-8-ethyl-naphthalene. To a solution of1,8-dibromonaphthalene (2.0 g, 6.99 mmol, 1.0 eq) and Pd(dppf)Cl₂ (367mg, 501 umol, 7.16 e⁻² eq) in THF (15.0 mL) was added diethyl zinc (1.0M in toluene, 3.50 mL, 0.50 eq) at −78° C. The mixture was stirred at−78-20° C. for 12 hours. After completion, the reaction mixture wasadded water (30.0 mL) and extracted with EA (30.0 mL×3). The organiclayer was dried over Na₂SO₄, filtered and concentrated. The residue wastriturated with PE (60.0 mL) and filtered. The filter cake was washedwith PE (10.0 mL×2), the mother liquid was concentrated. The obtainedproduct was purified by reversed phase flash column (C18, 0.1% FA inwater, 0-100% MeCN) to give 1-bromo-8-ethyl-naphthalene (600 mg, 2.45mmol, 35% yield, 96% purity) as yellow oil.

¹H NMR (400 MHz, Chloroform-d) δ 7.72-7.63 (m, 2H), 7.58 (dd, J=2.4, 7.2Hz, 1H), 7.30-7.23 (m, 2H), 7.13-7.04 (m, 1H), 3.43 (q, J=7.6 Hz, 2H),1.22 (t, J=7.6 Hz, 3H).

Step A: tert-butyl(2S)-2-(cyanomethyl)-4-[7-(8-ethyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of tert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(Intermediate 66, 300 mg, 636 umol, 1.0 eq), t-BuONa (183 mg, 1.91 mmol,3.0 eq), RuPhos (59.4 mg, 127 umol, 0.2 eq) and RuPhos-Pd-G3 (106 mg,127 umol, 020 eq) in toluene (5.0 mL) was added1-bromo-8-ethyl-naphthalene (299 mg, 1.27 mmol, 2.0 eq). The mixture wasstirred at 90° C. for 12 hours. After completion, the reaction mixturewas added water (10.0 mL) and extracted with EA (10.0 mL×3). The organiclayer was dried over Na₂SO₄, filtered and concentrated. The obtainedproduct was purified by reversed phase flash column (C18, 0.1% FA inwater, 0-60% MeCN) to give tert-butyl(2S)-2-(cyanomethyl)-4-[7-(8-ethyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(140 mg, 221 umol, 34% yield, 98% purity) as yellow oil. LCMS [ESI,M+1]: 626.

Step B:2-[(2S)-4-[7-(8-ethyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-2-(cyanomethyl)-4-[7-(8-ethyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(130 mg, 208 umol, 1.0 eq) in DCM (1.0 mL) was added TFA (1.54 g, 13.5mmol, 1.0 mL, 65.0 eq). The mixture was stirred at 25° C. for 10 min.After completion, the reaction mixture was concentrated under vacuum.The product2-[(2S)-4-[7-(8-ethyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(150 mg, crude, 2TFA) was obtained as yellow oil. LCMS [ESI, M+1]: 526.

Step C:2-[(2S)-4-[7-(8-ethyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-ethyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(150 mg, 199 umol, 1.0 eq, 2TFA) and DIEA (309 mg, 2.39 mmol, 416 uL,12.0 eq) in DCM (2.0 mL) was added prop-2-enoyl prop-2-enoate (37.7 mg,299 umol, 1.50 eq) at 0° C. The mixture was stirred at 0° C. for 0.5hour. After completion, the mixture was quenched with MeOH (1.0 mL) andconcentrated under vacuum. The obtained product was purified byprep-HPLC (column-Gemini 150*25 5 u; mobile phase: [water (0.05% ammoniahydroxide v/v)-ACN]; B %: 53%-83%, 12 min) to give title compound2-[(2S)-4-[7-(8-ethyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 360, 20.0 mg, 33.8 umol, 17% yield, 98% purity) as pink solid.LCMS [ESI, M+1]: 580.

¹H NMR (400 MHz, Chloroform-d) δ 7.74-7.64 (m, 2H), 7.46-7.35 (m, 2H),7.27-7.20 (m, 2H), 6.64-6.60 (m, 1H), 6.46-6.36 (m, 1H), 5.83 (br d,J=10.4 Hz, 1H), 5.20-4.50 (m, 1H), 4.45-4.33 (m, 1H), 4.31-4.19 (m, 1H),4.17-3.96 (m, 3H), 3.93-3.84 (m, 1H), 3.74 (br d, J=18.0 Hz, 1H),3.65-3.39 (m, 3H), 3.37-2.92 (m, 7H), 2.88-2.76 (m, 1H), 2.71-2.57 (m,2H), 2.47 (br d, J=4.8 Hz, 3H), 2.34-2.23 (m, 1H), 2.11-1.98 (m, 1H),1.80-1.72 (m, 3H), 1.17 (t, J=7.4 Hz, 3H).

Example 361

2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Insert: [(3R)-1-methylpyrrolidin-3-yl]methanol. To a solution oftert-butyl (3R)-3-(hydroxymethyl) pyrrolidine-1-carboxylate (1.0 g, 4.97mmol, 1.0 eq) in THF (20.0 mL) was added LiAlH₄ (377 mg, 9.94 mmol, 2.0eq). The mixture was stirred at 0° C. for 0.5 hour, then heated to 70°C. and stirred at 70° C. for 2 hours. After completion, the reactionmixture was quenched with saturated Na₂SO₄ aqueous (1.0 mL) andfiltered. The filter cake was washed with THF (10.0 mL). Then the motherliquid was concentrated to give [(3R)-1-methylpyrrolidin-3-yl]methanol(500 mg, 4.34 mmol, 87% yield) as colorless oil.

¹H NMR (400 MHz, Chloroform-d) δ 3.65 (dd, J=4.8, 10.0 Hz, 1H), 3.52(dd, J=5.6, 10.0 Hz, 1H), 3.05-2.69 (m, 2H), 2.63-2.53 (m, 1H),2.51-2.44 (m, 1H), 2.40-2.25 (m, 5H), 2.04-1.94 (m, 1H), 1.72-1.59 (m,1H).

Step A:tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.To a solution of [(3R)-1-methylpyrrolidin-3-yl] methanol (178 mg, 1.55mmol, 3.0 eq) in toluene (3.0 mL) was added t-BuONa (124 mg, 1.29 mmol,2.50 eq). The mixture was stirred at 0° C. for 0.5 hour. Then tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(300 mg, 516 umol, 1.0 eq) was added to the above mixture. Afteraddition, the mixture was stirred at 0° C. for 0.5 hour. Aftercompletion, the reaction mixture was added water (10.0 ml) and extractedwith EA (10.0 mL×3). The organic layer was dried over Na₂SO₄, filteredand concentrated. The obtained product was purified by reversed phaseflash (C18, 0.1% FA in water, 0-60% MeCN) to givetert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(220 mg, 342 umol, 66% yield, 98% purity) as yellow solid. LCMS [ESI,M+1]: 632.

Step B:2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(360 mg, 569 umol, 1.0 eq) in DCM (1.50 mL) was added TFA (2.31 g, 20.3mmol, 1.50 mL, 35.6 eq). The mixture was stirred at 25° C. for 0.5 hour.After completion, the reaction mixture was concentrated to give2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(450 mg, crude, 2TFA) as yellow oil.

Step C:2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(450 mg, 592 umol, 1.0 eq, 2TFA) and DIEA (918 mg, 7.10 mmol, 1.24 mL,12.0 eq) in DCM (4.0 mL) was added prop-2-enoyl prop-2-enoate (112 mg,888 umol, 1.50 eq). The mixture was stirred at 0° C. for 0.5 hour. Aftercompletion, the mixture was quenched with MeOH (1.0 mL) and concentratedunder vacuum. The obtained product was purified by prep-HPLC (column:Gemini 150*25 5 u; mobile phase: [water (0.04% NH₃·H₂O)-ACN]; B %:70%-82%, 10 min) to give title compound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 361, 32.6 mg, 53.8 umol, 9% yield, 97% purity) as gray solid.LCMS [ESI. M+1]: 586.

¹H NMR (400 MHz, Chloroform-d) δ 7.68 (br d, J=8.0 Hz, 1H), 7.54 (t,J=7.6 Hz, 1H), 7.45 (d, J=7.2 Hz, 1H), 7.41-7.32 (m, 1H), 7.26 (t, J=8.0Hz, 1H), 7.18-7.11 (m, 1H), 6.60-6.43 (m, 1H), 6.32 (br d, J=16.4 Hz,1H), 5.75 (br d, J=10.8 Hz, 1H), 5.15-4.50 (m, 1H), 4.41-4.28 (m, 1H),4.18-4.10 (m, 2H), 4.09-3.88 (m, 2H), 3.87-3.68 (m, 2H), 3.57-3.45 (m,1H), 3.42-3.26 (m, 1H), 3.25-2.87 (m, 5H), 2.86-2.74 (m, 1H), 2.73-2.57(m, 3H), 2.56-2.47 (m, 2H), 2.46-2.37 (m, 2H), 2.28 (s, 3H), 2.07-1.90(m, 1H). LCMS [ESI, M+1]: 586.

Example 362

2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A:tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl]-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.To a solution of 2-(1-piperidyl) ethanol (133 mg, 1.03 mmol, 137 uL, 3.0eq) in toluene (2.0 mL) was added t-BuONa (66.2 mg, 688 umol, 2.0 eq) at0° C. The mixture was stirred at 20° C. for 0.5 hour. Then tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(200 mg, 344 umol, 1.0 eq) was added to the above liquid at 0° C. Afteraddition, the mixture was stirred at 0° C. for 0.5 hour. Aftercompletion, the reaction mixture was added water (5.0 mL) and extractedwith EA (5.0 mL×3). The organic layer was dried over Na₂SO₄, filteredand concentrated. The obtained product was purified by columnchromatography (SiO₂, PE:EA=3:1-EA:MeOH=10:1) to givetert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(150 mg, 221 umol, 64% yield, 95% purity) as yellow oil. LCMS [ESI,M+1]: 646.

¹H NMR (400 MHz, Chloroform-d) δ 7.76 (d, J=8.0 Hz, 1H), 7.61 (t, J=7.8Hz, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.49-7.40 (m, 1H), 7.33 (t, J=7.8 Hz,1H), 7.27-7.17 (m, 1H), 4.64-4.61 (m, 1H), 4.48-4.36 (m, 3H), 4.14-3.92(m, 3H), 3.90-3.76 (m, 1H), 3.63-3.54 (m, 1H), 3.36 (br dd, J=3.6, 13.6Hz, 1H), 3.26-3.06 (m, 3H), 3.01-2.86 (m, 1H), 2.82-2.76 (m, 2H), 2.71(br d, J=6.8 Hz, 1H), 2.64-2.58 (m, 1H), 2.58-2.50 (m, 41H), 2.48-2.42(m, 1H), 2.06 (d, J=6.4 Hz, 1H), 1.64-1.57 (m, 5H), 1.52 (s, 9H).

Step B:2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(250 mg, 387 umol, 1.0 eq) in DCM (1.0 mL) was added TFA (1.54 g, 13.5mmol, 1.0 mL, 34.9 eq). The mixture was stirred at 25° C. for 0.5 hour.After completion, the reaction mixture was concentrated under vacuum.The product2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(300 mg, crude, 2TFA) was obtained as yellow oil. LCMS [ESI, M+1]: 546.

Step C:2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(300 mg, 388 umol, 1.0 eq, 2TFA) and DIEA (601 mg, 4.65 mmol, 810 uL,12.0 eq) in DCM (2.0 mL) was added prop-2-enoyl prop-2-enoate (73.3 mg,581 umol, 1.5 eq). The mixture was stirred at 0° C. for 0.5 hour. Aftercompletion, the mixture was quenched with MeOH (1.0 mL) and concentratedunder vacuum. The obtained product was purified by prep-HPLC (column:Gemini 150*25 5 u; mobile phase: [water (0.05% ammonia hydroxidev/v)-ACN]; B %: 55%-85%, 12 min) to give title compound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 362, 54.0 mg, 88.1 umol, 23% yield, 98% purity) as colorlessoil. LCMS [ESI, M+1]: 600.

¹H NMR (400 MHz, Chloroform-d) δ 7.76 (d, J=8.0 Hz, 1H), 7.62 (t, J=7.6Hz, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.49-7.39 (m, 1H), 7.34 (t, J=7.8 Hz,1H), 7.27-7.18 (m, 1H), 6.58-6.62 (m, 1H), 6.44-6.36 (m, 1H), 5.83 (brd, J=10.8 Hz, 1H), 5.15-4.55 (m, 1H), 4.51-4.36 (m, 3H), 4.20-3.97 (m,2H), 3.95-3.75 (m, 2H), 3.66-3.54 (m, 1H), 3.51-3.37 (m, 1H), 3.34-2.97(m, 4H), 2.94-2.67 (m, 4H), 2.65-2.57 (m, 1H), 2.55-2.48 (m, 4H),1.65-1.60 (m, 4H), 1.49-1.39 (m, 2H).

Example 363

2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R)-4-methylmorpholin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Insert: [(2R)-4-methylmorpholin-2-yl] methanol. To a solution oftert-butyl (2R)-2-(hydroxymethyl) morpholine-4-carboxylate (1.50 g, 6.90mmol, 1.0 eq) in THF (20.0 mL) was added LiAlH₄ (524 mg, 13.8 mmol, 2.0eq) in portions at 0° C. The mixture was stirred at 0° C. for 0.5 hour,then heated to 60° C. and stirred at 60° C. for 12 hours. Aftercompletion, the reaction mixture was quenched with saturated Na₂SO₄aqueous (1.50 mL) and filtered. The cake was washed with THF (20.0mL×2). Then the mother liquid was concentrated to give[(2R)-4-methylmorpholin-2-yl] methanol (800 mg, 6.10 mmol, 88% yield) asyellow oil.

¹H NMR (400 MHz, Chloroform-d) δ 3.92-3.86 (m, 1H), 3.73-3.52 (m, 4H),2.84-2.56 (m, 3H), 2.27 (s, 3H), 2.11 (dt, J=3.6, 11.6 Hz, 1H), 1.93 (t,J=10.8 Hz, 1H).

Step A: tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R)-4-methylmorpholin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.To a solution of [(2R)-4-methylmorpholin-2-yl]methanol (203 mg, 1.55mmol, 3.0 eq) in toluene (4.0 mL) was added t-BuONa (99.2 mg, 1.03 mmol,2.0 eq). The mixture was stirred at 0° C. for 0.5 hour. Then tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(300 mg, 516 umol, 1.0 eq) was added to the above mixture. The mixturewas stirred at 0° C. for 0.5 hour. After completion, the reactionmixture was added water (10.0 ml) and extracted with EA (10.0 mL×3). Theorganic layer was dried over Na₂SO₄, filtered and concentrated. Theobtained product was purified by column chromatography (SiO₂,PE:EA=3:1-EA:MeOH=10:1) to give tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R)-4-methylmorpholin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(250 mg, 366 umol, 71% yield, 95% purity) as yellow oil. LCMS [ESI,M+1]: 648.

¹H NMR (400 MHz, Chloroform-d) δ 7.75 (d, J=8.0 Hz, 1H), 7.61 (t, J=7.6Hz, 1H), 7.52 (d, J=7.6 Hz, 1H), 7.49-7.39 (m, 1H), 7.33 (t, J=7.8 Hz,1H), 7.26-7.17 (m, 1H), 4.68-4.53 (m, 1H), 4.48-4.31 (m, 2H), 4.29-4.19(m, 1H), 4.16-4.01 (m, 3H), 4.00-3.82 (m, 4H), 3.79-3.69 (m, 1H),3.63-3.53 (m, 1H), 3.36 (br dd, J=3.6, 13.6 Hz, 1H), 3.29-3.06 (m, 3H),3.01-2.86 (m, 2H), 2.83-2.64 (m, 3H), 2.63-2.45 (m, 1H), 2.36-2.28 (m,3H), 2.19 (dt, J=3.6, 11.6 Hz, 1H), 1.52 (s, 9H).

Step B:2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R)-4-methylmorpholin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R)-4-methylmorpholin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(240 mg, 370 umol, 1.0 eq) in DCM (1.0 mL) was added TFA (1.54 g, 13.5mmol, 1.0 mL, 36.5 eq). The mixture was stirred at 25° C. for 0.5 hour.After completion, the reaction mixture was concentrated to give2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R)-4-methylmorpholin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(300 mg, crude, 2TFA) as light red oil. LCMS [ESI, M+1]: 548.

Step C:2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R)-4-methylmorpholin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R)-4-methylmorpholin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(300 mg, 387 umol, 1.0 eq, 2TFA) and DIEA (599 mg, 4.64 mmol, 808 uL,12.0 eq) in DCM (2.0 mL) was added prop-2-enoyl prop-2-enoate (73.1 mg,580 umol, 1.50 eq). The mixture was stirred at 0° C. for 0.5 hour. Aftercompletion, the mixture was quenched with MeOH (1.0 mL) and concentratedunder vacuum. The obtained product was purified by prep-HPLC (column:Gemini 150*25 5 u; mobile phase: [water (0.04% NH₃·H₂O)-ACN]; B %:45%-75%, 10 min) to give title compound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R)-4-methylmorpholin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 363, 42.7 mg, 70.4 umol, 18% yield, 99% purity) as white solid.LCMS [ESI, M+1]: 602.

¹H NMR (400 MHz, Chloroform-d) δ 7.76 (d, J=8.0 Hz, 1H), 7.62 (t, J=7.2Hz, 1H), 7.55-7.50 (m, 1H), 7.49-7.40 (m, 1H), 7.34 (t, J=7.8 Hz, 1H),7.27-7.18 (m, 1H), 6.65-6.52 (m, 1H), 6.39 (br d, J=16.8 Hz, 1H), 5.83(br d, J=10.8 Hz, 1H), 5.25-4.53 (m, 1H), 4.48-4.32 (m, 2H), 4.30-4.21(m, 1H), 4.19-4.00 (m, 2H), 3.99-3.89 (m, 3H), 3.88-3.76 (m, 1H),3.75-3.68 (m, 1H), 3.64-3.55 (m, 1H), 3.52-3.35 (m, 1H), 3.31-2.98 (m,4H), 2.92-2.55 (m, 5H), 2.31 (s, 3H), 2.18 (dt, J=3.2, 11.4 Hz, 1H),2.02 (dt, J=1.6, 10.8 Hz, 1H).

Example 364

2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[3-methyl-2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step 1: 1-bromo-3-methoxy-2-(trifluoromethyl)benzene. To a solution ofMeOH (1.32 g, 41.2 mmol, 1.67 mL, 2 eq) in DMF (125 mL) was added NaH(1.65 g, 41.2 mmol, 60.0% purity, 2 eq). The mixture was stirred at 25°C. for 0.5 hour. Then to the mixture was added1-bromo-3-fluoro-2-(trifluoromethyl)benzene (5 g, 20.6 mmol, 1 eq) andstirred at 25° C. for 0.5 hour. The reaction mixture was quenched by icewater (20 mL). Water (300 mL) was added into the mixture and extractedwith MTBE (3×100 mL). The combined organic layers were washed with water(50 mL) and brine (50 mL). The combined organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated under vacuum. The residuewas purified by silica gel chromatography (PE) to give1-bromo-3-methoxy-2-(trifluoromethyl)benzene (5.28 g, 18.6 mmol, 91.0%yield, 90.0% purity) as a colorless oil.

¹H NMR (400 MHz, chloroform-d) δ=7.34-7.28 (m, 2H), 7.01-6.97 (m, 1H),3.91 (s, 3H).

Step 2: 1-methoxy-3-methyl-2-(trifluoromethyl)benzene. To the solutionof 1-bromo-3-methoxy-2-(trifluoromethyl)benzene (5.28 g, 20.7 mmol, 1eq), Cs₂CO₃ (20.2 g, 62.1 mmol, 3 eq), methylboronic acid (6.20 g, 104mmol, 5 eq) in dioxane (105 mL) and Water (21 mL) was added Pd(dppf)Cl₂(2.27 g, 3.11 mmol, 0.15 eq) under N₂. The suspension was degassed undervacuum and purged with N₂ several times. The mixture was stirred underN₂ at 100° C. for 6 hours. Water (50 mL) was added into the mixture. Themixture was diluted with EtOAc (30 mL) and extracted with EtOAc (100mL). The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by silica gelchromatography (PE) to give1-methoxy-3-methyl-2-(trifluoromethyl)benzene (3.2 g, 15.1 mmol, 73.1%yield, 90.0% purity) as a yellow oil.

¹H NMR (400 MHz, chloroform-d) δ=7.33 (t, J=8.0 Hz, 1H), 6.87 (br d,J=8.4 Hz, 1H), 6.83 (d, J=7.2 Hz, 1H), 3.88 (s, 3H), 2.49 (q, J=3.6 Hz,3H).

Step 3: 3-methyl-2-(trifluoromethyl)phenol. To the solution of1-methoxy-3-methyl-2-(trifluoromethyl)benzene (3.2 g, 16.8 mmol, 1 eq)in DCE (65 mL) was added BBr₃ (21.1 g, 84.1 mmol, 8.11 mL, 5 eq) at −40°C., the mixture was stirred at −40-−10° C. for 0.5 hour. The reactionmixture was quenched by Water (100 mL). The mixture was diluted withEtOAc (20 mL) and extracted with EtOAc (2×50 mL). The combined organiclayers were washed with brine (30 mL). The combined organic layers weredried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. Theresidue was purified by silica gel chromatography (PE:EtOAc from 1:0 to50:1) to give 3-methyl-2-(trifluoromethyl)phenol (740 mg, 4.08 mmol,24.2% yield, 97.0% purity) as a yellow solid.

¹H NMR (400 MHz, chloroform-d) δ=7.29-7.24 (m, 1H), 6.87-6.77 (m, 2H),5.95 (q, J=6.4 Hz, 1H), 2.46 (q, J=2.8 Hz, 3H).

Step 4: [3-methyl-2-(trifluoromethyl)phenyl] trifluoromethanesulfonate.To the solution of 3-methyl-2-(trifluoromethyl)phenol (600 mg, 3.41mmol, 1 eq), TEA (1.38 g, 13.6 mmol, 1.90 mL, 4 eq) in EtOAc (12 mL) wasadded Tf₂O (1.44 g, 5.11 mmol, 843 uL, 1.5 eq) at −40° C., the mixturewas stirred at −40° C. for 0.5 hour. The mixture was quenched by Water(10 mL). The mixture was diluted with EtOAc (10 mL) and extracted withEtOAc (30 mL). The organic layer was washed with brine (20 mL), driedover anhydrous Na₂SO₄, filtered and concentrated under vacuum. Theresidue was purified by silica gel chromatography (PE:EtOAc from 1:0 to100:1) to give [3-methyl-2-(trifluoromethyl)phenyl]trifluoromethanesulfonate (590 mg, 1.82 mmol, 53.0% yield, 95.0% purity)as a colorless oil.

¹H NMR (400 MHz, chloroform-d) δ=7.53-7.47 (m, 1H), 7.33 (d, J=7.6 Hz,1H), 7.29 (d, J=8.4 Hz, 1H), 2.57 (q, J=2.8 Hz, 3H).

Step A: benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[3-methyl-2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To the solution of benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(Intermediate 65, 600 mg, 973 umol, 1 eq),[3-methyl-2-(trifluoromethyl)phenyl] trifluoromethanesulfonate (450 mg,1.46 mmol, 1.5 eq), Cs₂CO₃ (951 mg, 2.92 mmol, 3 eq) and RuPhos (90.8mg, 195 umol, 0.2 eq) in toluene (12 mL) was added Pd₂(dba)₃ (89.1 mg,97.3 umol, 0.1 eq) under N₂. The suspension was degassed under vacuumand purged with N₂ several times. The mixture was stirred under N₂ at90° C. for 4 hours. Water (15 mL) was added into the mixture. Themixture was diluted with EtOAc (10 mL) and extracted with EtOAc (30 mL).The organic layer was washed with brine (20 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under vacuum. The residue was purifiedby silica gel chromatography (from PE:EtOAc=5:1˜1.1 toEtOAc:MeOH=1:0˜20:1). Then the residue was purified by reversed phaseflash column (ACN/Water (0.1% FA)=50.0%) to give benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[3-methyl-2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(240 mg, 354 umol, 36% yield, 98.0% purity) as a yellow oil. LCMS [ESI,M+1]: 664.

¹H NMR (400 MHz, chloroform-d) δ=7.41-7.35 (m, 6H), 7.18 (d, J=8.0 Hz,1H), 7.07 (d, J=7.6 Hz, 1H), 7.10-7.04 (m, 1H), 5.20 (s, 2H), 4.69 (brs, 1H), 4.38 (dd, J=5.2, 10.8 Hz, 1H), 4.16 (t, J=3.2 Hz, 1H), 4.05 (s,2H), 3.89 (br d, J=12.0 Hz, 1H), 3.30 (br s, 2H), 3.21-2.95 (m, 5H),2.92-2.62 (m, 6H), 2.52 (q, J=3.6 Hz, 3H), 2.48 (s, 3H), 2.33-2.24 (m,1H), 2.05-2.00 (m, 1H), 1.90-1.79 (m, 3H).

Step B: NH₃ was bubbled into MeOH (5 mL) for 5 minutes. To the solutionwas added benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[3-methyl-2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(240 mg, 362 umol, 1 eq), Pd/C (50 mg, 10.0% purity) under N₂. Thesuspension was degassed under vacuum and purged with H₂ several times.The mixture was stirred under H₂ (15 psi) at 30° C. for 0.5 hour. Thereaction mixture was filtered, the filtrate was concentrated widervacuum to give2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[3-methyl-2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(180 mg, 336 umol, 93.0% yield, 99.0% purity) as a brown oil which wasused for next step without further purification. LCMS [ESI, M+1]: 530.

Step C:2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[3-methyl-2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To the solution of2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[3-methyl-2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(170 mg, 321 umol, 1 eq) and TEA (97.4 mg, 963 umol, 134 uL, 3 eq) inDCM (3.5 mL) was added prop-2-enoyl chloride (43.6 mg, 482 umol, 39.3uL, 1.5 eq) at −40° C., the mixture was stirred at −40-30° C. for 0.5hour. The reaction mixture was quenched by Water (2 mL) and separated.The aqueous phase was extracted with EtOAc (4 mL). The combined organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by prep-HPLC (column: Gemini 150*25 5u; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %:55%-85%, 12 min) to give title compound2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[3-methyl-2-(trifluoromethyl)phenyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 364, 110 mg, 188 umol, 58.0% yield, 100% purity) as a whitesolid. LCMS [ESI, M+1]: 584.

¹H NMR (400 MHz, chloroform-d) δ=7.43-7.35 (m, 1H), 7.19 (d, J=8.4 Hz,1H), 7.08 (d, J=7.6 Hz, 1H), 6.59 (br s, 1H), 6.40 (dd, J=1.6, 16.8 Hz,1H), 5.83 (br d, J=10.4 Hz, 1H), 5.09 (br s, 1H), 4.64 (br s, 1H), 4.37(dd, J=4.8, 10.4 Hz, 1H), 4.18-4.08 (m, 2H), 4.06 (s, 2H), 3.96 (br d,J=12.4 Hz, 1H), 3.60 (br s, 1H), 3.30 (br s, 1H), 3.22-3.01 (m, 4H),2.98-2.62 (m, 5H), 2.52 (q, J=3.2 Hz, 3H), 2.48 (s, 3H), 2.33-2.23 (m,1H), 2.11-1.99 (m, 1H), 1.90-1.68 (m, 3H).

Example 365

2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Insert: 3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propan-1-ol. Toasolution of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane (500 mg, 3.69 mmol,1.0 eq, HCl), 3-bromopropan-1-ol (513 mg, 3.69 mmol, 333 uL, 1.0 eq) inCH₃CN (6.0 mL) was added K₂CO₃ (1.53 g, 11.1 mmol, 3.0 eq). The mixturewas stirred at 50° C. for 2 hours. After completion, the reactionmixture was filtered and the filtrate was evaporated. The residue waspurified by column chromatography (SiO₂, Ethyl acetate:MeOH=50:1 to20:1) to give3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propan-1-ol (195 mg,1.12 mmol, 30% yield, 90% purity) as colorless oil.

¹H NMR (400 MHz, Chloroform-d) δ 4.42 (s, 1H), 3.99 (d, J=8.0 Hz, 1H),3.82 (t, J=5.6 Hz, 2H), 3.65-3.61 (m, 1H), 3.53-3.45 (m, 2H), 2.99-2.92(m, 2H), 2.84-2.77 (m, 1H), 2.67-2.61 (m, 1H), 1.86-1.80 (m, 1H),1.79-1.58 (m, 3H).

Step A: tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.To a mixture of3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propan-1-ol (325 mg,2.06 mmol, 3.0 eq), t-BuONa (198 mg, 2.06 mmol, 3.0 eq) in toluene (2.0mL) was added a solution of tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(Intermediate 71, Step A, 400 mg, 688 umol, 1.0 eq) in toluene (2.0 mL)in portions, the mixture was stirred at 0° C. for 30 min under N₂atmosphere. After completion, the organic solvent was added water (10.0mL). The aqueous phase was extracted with ethyl acetate (3×10 mL).Combine extracts were washed with brine (20.0 mL), dried with Na₂SO₄,the solvent was then removed under vacuum. The residue was purified bycolumn chromatography (SiO₂, Petroleum ether:Ethyl acetate=3:1 to Ethylacetate:MeOH=20:1) to give tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(320 mg, 432 umol, 62% yield, 91% purity) as yellow solid. LCMS [ESI,M+1]: 674.

Step B:2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(340 mg, 504 umol, 1.0 eq) in dioxane (3.0 mL) was added HCl·dioxane(4.0 M, 3.0 mL, 23.8 eq). The mixture was stirred at 25° C. for 15 minunder N₂ atmosphere. After completion, the organic solvent was removedunder vacuum. The obtained product was adjusted with saturated NaHCO₃aqueous (10 mL), extracted with ethyl acetate (3×10 mL), the combinedorganic layer was dried over Na₂SO₄, filtered and concentrated. Thecrude product2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(270 mg, crude) was obtained as yellow solid and used into the next stepwithout further purification. LCMS [ESI, M+1]: 574.

Step C:2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(270 mg, 470 umol, 1.0 eq) in DCM (4.0 mL) was added TEA (143 mg, 1.41mmol, 196 uL, 3.0 eq) and prop-2-enoyl prop-2-enoate (178 mg, 1.41 mmol,3.0 eq) at 0° C. The mixture was stirred at 0° C. for 30 min under N₂atmosphere. After completion, the organic solvent was removed undervacuum. The residue was purified by column chromatography (Base Al₂O₃,Petroleum ether:Ethyl acetate=3:1 to 1:1), then the crude product wasconcentrated and repurified by prep-HPLC (column: Phenomenex Gemini150*25 mm*10 um: mobile phase: [water (0.05% ammonia hydroxidev/v)-ACN]; B %: 45%-75%, 12 min) and under lyophilization. Titlecompound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 365, 43.1 mg, 67.7 umol, 14% yield, 98% purity) was obtained asoff-white solid. LCMS [ESI, M+1]: 628.

¹H NMR (400 MHz, chloroform-d) δ 7.76 (d, J=9.6 Hz, 1H), 7.62 (t, J=7.6Hz, 1H), 7.50 (d, J=6.4 Hz, 1H), 7.47-7.40 (m, 1H), 7.34 (t, J=8.0 Hz,1H), 7.26-7.16 (m, 1H), 6.67-6.54 (m, 1H), 6.40 (d, J=16.8 Hz, 1H), 5.82(d, J=10.8 Hz, 1H), 5.16-5.03 (m, 1H), 4.48-4.40 (m, 1H), 4.38-4.34 (m,3H), 4.22-4.08 (m, 1H), 4.07-3.99 (m, 2H), 3.97-3.74 (m, 2H), 3.64-3.55(m, 2H), 3.54-3.35 (m, 2H), 3.31-3.20 (m, 1H), 3.19-3.14 (m, 1H),3.13-2.99 (m, 2H), 2.92 (d, J=10.4 Hz, 1H), 2.89-2.81 (m, 1H), 2.80-2.76(m, 1H), 2.75-2.68 (m, 1H), 2.64-2.57 (m, 1H), 2.52 (d, J=10.0 Hz, 1H),1.98-1.89 (m, 2H), 1.85 (d, J=9.2 Hz, 1H), 1.74-1.70 (m, 2H).

Example 366

2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Insert: To a solution of O1-tert-butyl O2-methyl(2S)-4,4-difluoropyrrolidine-1,2-dicarboxylate (300 mg, 1.13 mmol, 1.0eq) in THF (8.0 mL) was added LiAlH₄ (129 mg, 3.39 mmol, 3.0 eq). Themixture was stirred at −40° C. for 1 hour. Then the mixture was stirredat 80° C. for 2 hours under N₂ atmosphere. After completion, thereaction mixture was quenched with saturated Na₂SO₄ aqueous solution(6.0 mL), dried with Na₂SO₄. Then the mixture was filtered and thefiltrate was concentrated. [(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methanol (165 mg, crude) was obtained as colorless oil and used into thenext step without further purification.

Step A: tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.To a solution of [(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methanol(156 mg, 1.03 mmol, 3.0 eq) in toluene (2.0 mL) was added t-BuONa (99.2mg, 1.03 mmol, 3.0 eq) at 0° C. and a solution of tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(200 mg, 344 umol, 1.0 eq) in toluene (1.0 mL) dropwise at 0° C. underN₂. The reaction mixture was stirred at 0° C. for 30 min. Aftercompletion, the organic solvent was added water (10.0 mL), extractedwith ethyl acetate (3×10 mL). Combine extracts were washed with brine(20.0 mL), dried with Na₂SO₄, filtered and the filtrate wasconcentrated. The residue was purified by column chromatography (SiO₂,Petroleum ether:Ethyl acetate=5:1 to 1:1) to give tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(160 mg, 230 umol, 67% yield, 96% purity) as yellow solid. LCMS [ESI,M-+1]668.

Step B:2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(137 mg, 205 umol, 1.0 eq) in dioxane (1.0 mL) was added HCl·dioxane (4M, 1.0 mL, 19.5 eq). The mixture was stirred at 25° C. for 15 min underN₂ atmosphere. After completion, the organic solvent was removed undervacuum. The obtained product was adjusted with saturated NaHCO₃ aqueous(10 mL), extracted with ethyl acetate (3×10 mL), dried over Na₂SO₄,filtered and concentrated. The crude product2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(110 mg, crude) was obtained as yellow solid and used into the next stepwithout further purification. LCMS [ESI, M+1]: 568.

Step C:2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(110 mg, 194 umol, 1.0 eq) in DCM (3.0 mL) was added TEA (196 mg, 1.94mmol, 270 uL, 10.0 eq) and prop-2-enoyl prop-2-enoate (73.3 mg, 581umol, 3.0 eq) at 0° C. The mixture was stirred at 0° C. for 30 min underN₂ atmosphere. After completion, the reaction mixture was quenched withmethanol (6.0 mL) and the mixture was removed under vacuum. The residuewas purified by prep-HPLC (column: Phenomenex Gemini 150×25 mm×10 um;mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 55%-85%,12 min) and under lyophilization. Title compound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 366, 34.1 mg, 54.5 umol, 28% yield, 99% purity) was obtained asoff-white solid. LCMS [ESI, M+1]: 622.

¹H NMR (400 MHz, chloroform-d) δ 7.76 (d, J=8.0 Hz, 1H), 7.63 (t, J=7.2Hz, 1H), 7.50 (d, J=7.6 Hz, 1H), 7.49-7.42 (m, 1H), 7.34 (t, J=8.0 Hz,1H), 7.26-7.19 (m, 1H), 6.63-6.57 (m, 1H), 6.40 (d, J=16.8 Hz, 1H), 5.84(d, J=10.4 Hz, 1H), 5.02-4.98 (m, 1H), 4.49-4.37 (m, 2H), 4.31-4.22 (m,1H), 4.19-3.97 (m, 2H), 3.96-3.89 (m, 1H), 3.88-3.77 (m, 1H), 3.76-3.65(m, 1H), 3.64-3.55 (m, 1H), 3.52-3.37 (m, 2H), 3.36-3.10 (m, 3H),3.07-2.95 (m, 2H), 2.94-2.80 (m, 1H), 2.79-2.48 (m, 4H), 2.47-2.45 (m,3H), 2.36-2.24 (m, 1H).

Example 367

2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-morpholinobut-2-enoyl]piperazin-2-yl]acetonitrile

Step A:2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(Intermediate 71, Step A, 200 mg, 316 umol, 1.0 eq) in dioxane (1.5 mL)was added HCl·dioxane (4 M, 1.5 mL, 19.0 eq). The mixture was stirred at25° C. for 0.5 hour under N₂ atmosphere. After completion, the organicsolvent was removed under vacuum. The obtained product was adjusted withsaturated NaHCO₃ aqueous (10 mL), extracted with ethyl acetate (3×10mL), dried over Na₂SO₄, filtered and the filtrate was concentrated. Thecrude product2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(130 mg, crude) was obtained as yellow solid and used into the next stepwithout further purification. LCMS [ESI, M+1]: 532.

Step B:2-[(2S)-1-[(E)-4-bromobut-2-enoyl]-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(150 mg, 282 umol, 1.0 eq) in DCM (3.0 mL) was added Pyridine (446 mg,5.64 mmol, 455 uL, 20.0 eq) and (E)-4-bromobut-2-enoyl chloride (155 mg,846 umol, 3.0 eq). The mixture was stirred at 0° C. for 0.5 hour. Aftercompletion, the mixture was concentrated. The crude product2-[(2S)-1-[(E)-4-bromobut-2-enoyl]-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(190 mg, crude) was obtained as yellow solid and used into the next stepwithout further purification LCMS [ESI, M+1-]: 680.

Step C:2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-morpholinobut-2-enoyl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-1-[(E)-4-bromobut-2-enoyl]-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(190 mg, 280 umol, 1.0 eq), KI (9.29 mg, 56.0 umol, 0.20 eq) and K₂CO₃(387 mg, 2.80 mmol, 10.0 eq) in DCM (5.0 mL) was added morpholine (146mg, 1.68 mmol, 148 uL, 6.0 eq). The mixture was stirred at 0° C. for 0.5hour. After completion, the reaction mixture was quenched with methanol(10.0 mL) and the mixture was removed under vacuum. The residue waspurified by prep-HPLC (column: Phenomenex Gemini 150*25 mm*10 um: mobilephase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 60%-90%, 12 min)and then under lyophilization. The title compound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-morpholinobut-2-enoyl]piperazin-2-yl]acetonitrile(EXAMPLE 367, 31.6 mg, 45.2 umol, 16% yield, 98% purity) was obtained asyellow solid. LCMS [ESI, M+1]: 685.

¹H NMR (400 MHz, chloroform-d) δ 7.78-7.73 (m, 1H), 7.62 (t, J=7.6 Hz,1H), 7.55-7.51 (m, 1H), 7.48-7.41 (m, 1H), 7.34 (t, J=7.8 Hz, 1H),7.26-7.18 (m, 1H), 7.02-6.91 (m, 1H), 6.55-6.42 (m, 1H), 5.15-5.01 (m,1H), 4.47-4.34 (m, 2H), 4.20-4.13 (m, 1H), 4.12-4.04 (m, 1H), 3.95-3.79(m, 2H), 3.78-3.65 (m, 5H), 3.62-3.63 (m, 1H), 3.52-3.36 (m, 1H),3.30-3.14 (m, 4H), 3.13-2.97 (m, 3H), 2.88-2.77 (m, 1H), 2.73-2.53 (m,3H), 2.52-2.46 (m, 7H), 2.34-2.22 (m, 1H), 2.11-1.99 (m, 1H), 1.88-1.70(m, 3H).

Example 368

2-((2S,5S)-1-acryloyl-5-methyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: ((2R,5S)-5-methylpiperazin-2-yl)methanol: Cyclo(L-Ala-L-Ser)(400 mg, 2.53 mmol) was diluted with borane-tetrahydrofuran complex(18716 μl, 18.7 mmol), placed under nitrogen and heated to 70° C. Afterstirring for 12 hours, the reaction was allowed to cool. The reactionwas cooled to 0° C. in an ice bath followed by the slow dropwiseaddition of MeOH (5116 μl, 126 mmol) followed by the addition of HCl(1096 μl, 6.58 mmol). After stirring for one hour, the reaction wasconcentrated to afford ((2R,5S)-5-methylpiperazin-2-yl)methanol (328 mg,2.52 mmol, 99.6% yield).

Step B: tert-butyl(6S,8aR)-6-methyl-3-oxotetrahydro-3H-oxazolo[3,4-d]pyrazine-7(1H)-carboxylate:((2R,5S)-5-methylpiperazin-2-yl)methanol (500 mg, 3.84 mmol) was dilutedwith methanol (5 mL), placed under nitrogen and cooled to 0° C. TEA(2141 μl, 15.4 mmol) was added followed by BOC-Anhydride (2675 μl, 11.5mmol)(in methanol 5 mL, over 15 minutes). The reaction was kept <10° C.for 1 hour and then the ice bath was removed. After 1 additional hour,the reaction was heated to 50° C. After stirring at 50° C. for 12 hours,the reaction was concentrated to afford tert-butyl(6S,8aR)-6-methyl-3-oxotetrahydro-3H-oxazolo[3,4-a]pyrazine-7(1H)-carboxylate(980 mg, 3.82 mmol, 99.6% yield).

Step C: tert-butyl(2S,5R)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate: Tert-butyl(6S,8aR)-6-methyl-3-oxotetrahydro-3H-oxazolo[3,4-a]pyrazine-7(1H)-carboxylate(980 mg, 3.82 mmol) was diluted with ethanol (10047 μl, 172 mmol)followed by the addition of NaOH (9559 μl, 19.1 mmol). The reaction wasplaced under nitrogen, heated to 95° C. and stirred for 4 hours. TLC(methanol/DCM/NH4OH, 10/89/1) staining with KMNO4 indicated thedisappearance of a slightly higher rf spot. The reaction was allowed tocool, and then placed in an ice bath. The pH was adjusted to ˜9 with 2NHCl and then extracted twice with DCM. The DCM was dried over MgSO4,filtered and concentrated to afford tert-butyl(2S,5R)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate (850 mg, 3.69mmol, 96.5% yield).

Step D: 1-benzyl 4-(tert-butyl)(2R,5S)-2-(hydroxymethyl)-5-methylpiperazine-1,4-dicarboxylate:Tert-butyl (2S,5R)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate(350 mg, 1.52 mmol) was diluted with THF (4 mL), placed under nitrogenand cooled to 0° C. NaOH (1672 μl, 1.67 mmol) was added followed by theaddition of benzyl chloroformate (228 μl, 1.52 mmol). After stirring for2 hours, the reaction was diluted with ethyl acetate and water. Thewater was extracted two more times and the ethyl acetate was combined,dried over MgSO4, filtered and concentrated. The material was purifiedon silica gel eluting with 10-80% ethyl acetate/hexanes to afford1-benzyl 4-(tert-butyl)(2R,5S)-2-(hydroxymethyl)-5-methylpiperazine-1,4-dicarboxylate (300 mg,0.823 mmol, 54.2% yield) ESI+APCI MS m/z 265.1 [M+H]⁺ (minus boc).

Step E: 1-benzyl 4-(tert-butyl)(2R,5S)-5-methyl-2-(((methylsulfonyl)oxy)methyl)piperazine-1,4-dicarboxylate:1-benzyl4-(tert-butyl)(2R,5S)-2-(hydroxymethyl)-5-methylpiperazine-1,4-dicarboxylate(300 mg, 0.823 mmol) was diluted with DCM (4 mL), placed under nitrogenand cooled to 0° C. DIEA (216 μl, 1.23 mmol) was added followed by theaddition of methanesulfonyl chloride (70.1 μl, 0.905 mmol). Afterstirring for 2 hours at 0° C., the reaction was diluted with DCM andsaturated sodium bicarbonate. The layers were separated and the ethylacetate was dried over MgSO4, filtered and concentrated. The materialwas purified on silica gel eluting with 10-50% ethyl acetate/hexanes toafford 1-benzyl 4-(tert-butyl)(2R,5S)-5-methyl-2-(((methylsulfonyl)oxy)methyl)piperazine-1,4-dicarboxylate(290 mg, 0.655 mmol, 79.6% yield).

Step F: 1-benzyl 4-(tert-butyl)(2S,5S)-2-(cyanomethyl)-5-methylpiperazine-1,4-dicarboxylate: 1-benzyl4-(tert-butyl)(2R,5S)-5-methyl-2-(((methylsulfonyl)oxy)methyl)piperazine-1,4-dicarboxylate(290 mg, 0.655 mmol) was diluted with DMA (4 mL) followed by theaddition of NaCN (64.2 mg, 1.31 mmol). The reaction was heated to 55° C.and stirred for 12 hours. The reaction was allowed to cool, diluted withMTBE and washed with saturated sodium bicarbonate, water and brine. TheMTBE was dried over MgSO4, filtered and concentrated. The material waspurified on silica gel eluting with 10-50% ethyl acetate/hexanes toafford 1-benzyl 4-(tert-butyl)(2S,5S)-2-(cyanomethyl)-5-methylpiperazine-1,4-dicarboxylate (200 mg,0.536 mmol, 81.7% yield). ESI+APCI MS m/z 274.2 [M+H]⁺ (minus boc).

Step G: benzyl (2S,5S)-2-(cyanomethyl)-5-methylpiperazine-1-carboxylate:1-benzyl 4-(tert-butyl)(2S,5S)-2-(cyanomethyl)-5-methylpiperazine-1,4-dicarboxylate (200 mg,0.536 mmol) was diluted with DCM (2 mL) followed by the addition of HCl(669 μl, 2.68 mmol). After stirring for 3 hours, the reaction wasconcentrated to afford benzyl(2S,5S)-2-(cyanomethyl)-5-methylpiperazine-1-carboxylate (146 mg, 0.534mmol, 99.7% yield). ESI+APCI MS m/z 274.1 [M+H]⁺.

Step H: tert-butyl4-((2S,5S)-4-(benzyloxy)carbonyl)-5-(cyanomethyl)-2-methylpiperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H-carboxylate:tert-Butyl2,4-dichloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (211mg, 0.695 mmol) was diluted with DMA (4 mL) followed by the addition ofbenzyl (2S,5S)-2-(cyanomethyl)-5-methylpiperazine-1-carboxylate (190 mg,0.695 mmol) and DIEA (364 μl, 2.09 mmol). The reaction was allowed tostir at ambient temperature for 12 hours. Very little product wasdetected so the reaction was heated to 75° C. for an additional 12hours. The reaction was allowed to cool, diluted with ethyl acetate andwater. The ethyl acetate was washed with water, brine, dried over MgSO4,filtered and concentrated. The material was purified on silica geleluting with 10-50% ethyl acetate/hexanes to afford tert-butyl4-((2S,5S)-4-((benzyloxy)carbonyl)-5-(cyanomethyl)-2-methylpiperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(53 mg, 0.0980 mmol, 14.1% yield). ESI+APCI MS m/z 541.2 [M+H]⁺.

Step I: benzyl(2S,5S)-4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)-5-methylpiperazine-1-carboxylate:Tert-butyl4-((2S,5S)-4-((benzyloxy)carbonyl)-5-(cyanomethyl)-2-methylpiperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(53 mg, 0.098 mmol) was diluted with DCM followed by the addition of HCl(122 μl, 0.49 mmol). After stirring for 4 hours, the reaction wasconcentrated to afford benzyl(2S,5S)-4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)-5-methylpiperazine-1-carboxylate(43 mg, 0.098 mmol, 100% yield). ESI+APCI MS m/z 441.1 [M+H]⁺.

Step J: benzyl(2S,5S)-4-(2-chloro-7-(naphthen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl-5-methylpiperazine-1-carboxylate:Benzyl(2S,5S)-4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)-5-methylpiperazine-1-carboxylate(43 mg, 0.0975 mmol), 1-iodonaphthalene (124 mg, 0.488 mmol), Cs₂CO₃(95.3 mg, 0.293 mmol) andMethanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II)(12.5 mg, 0.0146 mmol) were diluted with DMA (600 uL), purged withargon, sealed and heated to 92° C. After stirring for 12 hours, thereaction was allowed to cool, diluted with ethyl acetate and water. Thelayers were separated and the ethyl acetate was washed with brine, driedover MgSO4, filtered and concentrated. The material was purified onsilica gel eluting with 10-50% ethyl acetate/hexanes to afford benzyl(2S,5S)-4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)-5-methylpiperazine-1-carboxylate(26.5 mg, 0.0467 mmol, 47.9% yield). ESI+APCI MS m/z 567.2 [M+H]⁺.

Step K:2-((2S,5S)-5-methyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:benzyl(2S,5S)-4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)-5-methylpiperazine-1-carboxylate(26.5 mg, 0.0467 mmol),(s)-(dicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)-5-phosphanyl)(2′-(methylamino)-[1,1′-biphenyl]-2-yl)palladium(III)methanesulfonate (7.96 mg, 0.00935 mmol) and Cs₂CO₃ (76.1 mg, 0.234mmol) were diluted with DMA (300 uL) followed by the addition ofN-Methyl-1-prolinol (21.5 mg, 0.187 mmol). The reaction was purged withargon, sealed and heated to 90° C. After stirring for 12 hours, thereaction was allowed to cool, diluted with ethyl acetate and water. Theethyl acetate was dried over MgSO4, filtered and concentrated. Thematerial was purified on silica gel eluting with 10% methanol/DCM (1%NH4OH) to afford benzyl(2S,5S)-2-(cyanomethyl)-5-methyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(8 mg, 0.0124 mmol, 26.5% yield) and2-((2S,5S)-5-methyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(10 mg, 0.0195 mmol, 41.8% yield). ESI+APCI MS m/z 512.3 [M+H]⁺.

Step L:2-((2S,5S-1-acryloyl-5-methyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:2-((2S,5S)-5-methyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(10 mg, 0.020 mmol) was diluted with DCM (200 uL) followed by theaddition of DIEA (6.8 μl, 0.039 mmol). The reaction was placed undernitrogen and cooled to 0° C. acryloyl chloride (1.8 μl, 0.021 mmol) wasadded and the reaction was stirred for 2 hours. The reaction was pouredinto a 10% sodium bicarbonate solution and extracted with DCM. The DCMwas dried over MgSO4, filtered and concentrated. The material waspurified on silica gel eluting with 10% methanol/DCM (1% NH4OH) toafford title compound2-((2S,5S)-1-acryloyl-5-methyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(EXAMPLE 368.6 mg, 0.011 mmol, 54% yield). ESI+APCI MS m/z 566.3 [M+H]⁺.

Example 369

2-((S)-4-(2-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-acryloylpiperazin-2-yl)acetonitrile

Step A: tert-butyl(S)-4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:Benzyl (S)-2-(cyanomethyl)piperazine-1-carboxylate hydrochloride (10 g,34 mmol) was dissolved in DMA (68 ml, 34 mmol). To the solution was nextadded tert-butyl2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (9.3g, 30 mmol) followed by Hunig's Base (24 ml, 135 mmol) and the reactionstirred at room temperature for 1 hour. The reaction was next pouredinto basic water and extracted with MTBE. The organics were washed withadditional water, brine, dried over Na₂SO₄ and concentrated in vacuo.The material was chromatographed using 10% to 70% EtOAc:Hexane as eluentto give tert-butyl(S)-4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(12 g, 23 mmol, 67% yield). ESI+APCI MS m/z 527.2 [M+H]⁺.

Step B: benzyl(S)-4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:Tert-butyl(S)-4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(1 g, 2 mmol) was dissolved in DCM (19 ml, 2 mmol) and treated withHydrochloric Acid (4.0 M solution in 1,4-dioxane) (2 ml, 9 mmol). Thereaction stirred at room temperature for 1 hour. The reaction wasconcentrated in vacuo and resuspended in DCM. The suspension was washedwith 1M NaOH. The aqueous layer was extracted with DCM (2×). Thecombined organics were dried over Na₂SO₄, concentrated in vacuo andtaken forward as crude benzyl(S)-4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(0.8 g, 2 mmol, 99% yield). ESI+APCI MS m/z 427.1 [M+H]⁺.

Step C: benzyl(S)-4-(2-chloro-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:Tris(dibenzylideneacetone)dipalladium(0) (343 mg, 0.375 mmol) and2-(Dicyclohexylphosphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (357 mg,0.750 mmol) were dissolved in 1,4-dioxane (18740 μl, 1.87 mmol) andpurged under Argon for 5 minutes. The reaction stirred at 100° C. underargon for an additional 15 min. To the reaction was added benzyl(S)-4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(800 mg, 1.87 mmol), 1-bromo-8-methylnaphthalene (1243 mg, 5.62 mmol),and cesium carbonate (1832 mg, 5.62 mmol) under Argon. The reaction wascapped under Argon and stirred at 100° C. over night. The reaction wascooled to room temperature and filtered through GF/F paper. The filtratewas concentrated in vacuo and purified by normal phase chromatography onthe CombiFlash eluting with 0%-15% DCM:MeOH (+2% NH₄OH modifier) to givebenzyl(S)-4-(2-chloro-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(378 mg, 0.667 mmol, 35.6% yield). ESI+APCI MS m/z 567.2 [M+H]⁺.

Step D: benzyl(S)-4-(2-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:In a round bottom flask, a solution of benzyl(S)-4-(2-chloro-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(0.3 g, 0.529 mmol) in dioxane (5.29 ml, 0.529 mmol) was sparged withArgon. 3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propan-1-ol(0.250 g, 1.59 mmol), Cs₂CO₃ (0.517 g, 1.59 mmol),Tris(dibenzylideneacetone)dipalladium (0) (0.0969 g, 0.106 mmol) and9,9-Dimethyl-4,5-Bis(Dipheyl-Phosphino)Xanthene (0.122 g, 0.212 mmol)were sequentially added under Argon and sparged for an additional 5minutes. The reaction mixture was capped and heated at 100° C. for 2hours. The reaction was filtered through GF/F paper and concentrated invacuo. The concentrate was purified by silica gel eluting with 0-12%MeOH in DCM with 2% NH₄OH to provide benzyl(S)-4-(2-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(0.155 g, 0.225 mmol, 42.6% yield). ESI+APCI MS m/z 688.3 [M+H]⁺.

Step E:2-((S)-4-(2-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:A solution of benzyl(S)-4-(2-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(155 mg, 0.225 mmol) in EtOH (2253 μl, 0.225 mmol) and THF (2253 μl,0.225 mmol) and EtOH (2253 μl, 0.225 mmol) was purged with N₂ for 5minutes. To this solution was added Palladium (60.0 mg, 0.0563 mmol)(Degussa Type, 10 wt %, 50% H₂O), and was immediately capped and purgedwith N₂ for an additional 5 minutes. The solution then stirred under anatmosphere of H₂. The mixture was then diluted with MeOH and filteredthrough packed celite. The filtrate was then concentrated in vacuo toprovide2-((S)-4-(2-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(98 mg, 0.177 mmol, 78.5% yield). This was taken forward as crude.ESI+APCI MS m/z 554.3 [M+H]⁺.

Step F:2-((S)-4-(2-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-acryloylpiperazin-2-yl)acetonitrile:To a suspension of2-((S)-4-(2-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(98 mg, 0.177 mmol) in dichloromethane (1770 μl, 0.177 mmol) at ambienttemperature was added Acyloyl Chloride (14.4 μl, 0.177 mmol) followed byHunig's base (61.8 μl, 0.354 mmol). The reaction was then stirred atambient temperature for 2 hours. The reaction mixture was concentratedin vacuo. The concentrate was resuspended in a 60:40 mixture of ACN:H₂Oand purified on the Gilson (reverse prep HPLC), eluting with 5->95%ACN/0.1% TFA in water/0.1% TFA. Fractions containing product werecombined and partitioned between saturated bicarb and DCM. The aqueouslayer was extracted with DCM two more times. The organic layers werecombined, dried over Na₂SO₄ and concentrated in vacuo to give titlecompound2-((S)-4-(2-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-acryloylpiperazin-2-yl)acetonitrile(EXAMPLE 369, 63.5 mg, 0.104 mmol, 59.0% yield). ESI+APCI MS m/z 608.3[M+H]⁺.

Example 370

(S)-2-(1-acryloyl-4-(7-(8-methylnaphthalen-1-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

(S)-2-(1-acryloyl-4-(7-(8-methylnaphthalen-1-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:The title compound was prepared following EXAMPLE 369 substitutingN-Hydroxypropanylmorpholine for3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propan-1-ol and alsosubstitutingMethanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II)for Tris(dibenzylideneacetone)dipalladium (0) and9,9-Dimethyl-4,5-Bis(Dipheyl-Phosphino)Xanthene in Step D. ESI+APCI MSm/z 596.3 [M+H]⁺.

Example 371

(S)-3-((4-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)-N,N-dimethylpropanamide

(S)-3-((4-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)-N,N-dimethylpropanamide:The title compound was prepared following EXAMPLE 369 substituting3-Hydroxy-N,N-dimethylpropanamide for3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propan-1-ol and alsosubstitutingMethanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II)for Tris(dibenzylideneacetone)dipalladium (0) and9,9-Dimethyl-4,5-Bis(Dipheyl-Phosphino)Xanthene in Step D. ESI+APCI MSm/z 568.3 [M+H]⁺.

Example 372

2-((S)-1-((E)-but-2-enoyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A:2-((S)-1-((E)-but-2-enoyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(30 mg, 0.05863 mmol) and 3-(E)-but-2-enoic acid (6.562 mg, 0.07622mmol) were diluted with DMF (400 uL) followed by the addition of DIEA(20.48 μl, 0.1173 mmol) and 1-propanephosphonic acid cyclic anhydride(52.35 μl, 0.08795 mmol). After stirring for 12 hours, the reaction wasdiluted with ethyl acetate and saturated sodium bicarbonate. The layerswere separated and the ethyl acetate was dried over MgSO4, filtered andconcentrated. The material was purified on silica gel eluting with 10%methanol/DCM (1% NH₄OH) to afford title compound2-((S)-1-((E)-but-2-enoyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(EXAMPLE 372, 10 mg, 0.01725 mmol, 29.42% yield). ESI+APCI MS m/z 580.3[M+H]⁺.

Example 373

2-(1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(3-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: Benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(3-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:In a microwave tube benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(100 mg, 0.198 mmol) was dissolved in dioxane (98.9 μl, 0.198 mmol) andtreated with cesium carbonate (129 mg, 0.396 mmol), and2-Fluoro-3-(trifluoromethyl)pyridine (163 mg, 0.989 mmol). The tube wasthen capped and heated to 90° C. for 12 hr. The reaction was cooled andfiltered through GF/F paper and the filtrate was concentrated. Theresidue was purified by silica chromatography (0-12% MeOH in DCM with0.25% NH4OH) to provide benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(3-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(70 mg, 0.11 mmol, 54%).

Step B:2-(1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy-7-(3-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.The title compound was prepared following EXAMPLE 375, Steps F-Gsubstituting benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(3-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatefor benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(3-(trifluoromethyl)pyridin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatein EXAMPLE 375 Step F. ESI+APCI MS m/z 571.3 [M+H]⁺.

Example 374

2-(1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(2-(2,2,2-trifluoroethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-(1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(2-(2,2,2-trifluoroethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:Was prepared following Example 375, Steps E-G, substituting1-bromo-2-(2,2,2-trifluoroethyl)benzene for4-Bromo-3-(trifluoromethyl)pyridine hydrobromide in Step E. ESI+APCI MSm/z 584.3 [M+H]⁺.

Example 375

2-(1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(3-(trifluoromethyl)pyridin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: tert-butyl2-chloro-4-(3-(cyanomethyl)piperazin-1-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:tert-butyl2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (8.0g, 26.3 mmol), Hunig's base (22.9 ml, 132 mmol) and2-(piperazin-2-yl)acetonitrile dihydrochlorid (5.21 g, 26.3 mmol) wereplaced in DMA (75 mL) and stirred at rt for 20 min. Water was added andthe mixture was extracted with EtOAc (3×100 mL). The extracts werecombined and washed with water (3×50 mL) then was dried with sodiumsulfate. The solids were filtered and the filtrate was concentrated toprovide crude tert-butyl2-chloro-4-(3-(cyanomethyl)piperazin-1-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate.ESI+APCI MS m/z 337.1 [M+H]⁺.

Step B: tert-butyl4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:tert-butyl2-chloro-4-(3-(cyanomethyl)piperazin-1-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(10.50 g, 26.725 mmol) and TEA (5.5876 ml, 40.088 mmol) were placed inTHF (100 mL) and was cooled to 0 C. Benzyl carbonochloridate (5.6518 ml,40.088 mmol) was added and the reaction was stirred at 0 C for 30 min.Water was added and the mixture was extracted with DCM (3×50 mL). Theextracts were combined and concentrated. The resulting residue waspurified by silica gel (0-60% EtOAc in hex) to provide tert-butyl4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(12.939 g, 24.551 mmol, 91.865% yield). ESI+APCI MS m/z 527.2 [M+H]⁺.

Step C: tert-butyl4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:In a conical bottom vial, a solution of tert-butyl(S)-4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(3.28 g, 6.22 mmol) in dioxane (62.2 ml, 6.22 mmol) was sparged withargon and (S)-(1-methylpyrrolidin-2-yl)methanol (2.15 g, 18.7 mmol),Cs2CO3 (6.08 g, 18.7 mmol),Methanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II)(0.795 g, 0.934 mmol) were sequentially added under argon and spargedfor an additional 5 min. The reaction mixture was capped and heated at100° C. for 18 hr. The reaction was cooled and water was added. Themixture was extracted with DCM (3×15 mL) and the extracts were combinedand concentrated. The resulting residue was purified by silica gel(0-12% MeOH in DCM with 0.25% NH4OH) to provide tert-butyl4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(2.65 g, 4.37 mmol, 70.3% yield) ESI+APCI MS m/z 606.3 [M+H]⁺.

Step D: benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:tert-butyl4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(0.6 g, 1.0 mmol) was dissolved in dichloromethane (10 ml, 1.0 mmol) andtreated with hydrochloric acid (4.0 M solution in 1,4-dioxane (1 ml, 5mmol) and the reaction was stirred at room temperature for 1 hour. Thereaction was next concentrated in vacuo and the material partitionedbetween EtOAc and basic water and the layers separated. The organicswere next washed with brine, dried over Na₂SO₄ and concentrated in vacuoto give benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.4 g, 0.8 mmol, 80% yield). ESI+APCI MS m/z 506.2 [M+H]⁺.

Step E: benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(3-(trifluoromethyl)pyridin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate.To a vial was added Cesium carbonate (193 mg, 0.593 mmol), benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(60 mg, 0.119 mmol) and Rhuphos Pd G3 (9.92 mg, 0.0119 mmol), and4-Bromo-3-(trifluoromethyl)pyridine hydrobromide (93.4 mg, 0.356 mmol).the vial was sealed and the 1,4-dioxane (1187 μl, 0.119 mmol) addedthrough a septum. Ar was bubbled through the mixture for 5 minutes andthen the mixture was heated to 70° C. for 7 h. the reaction was cooled,filtered through qualitative paper and concentrated. The yellow solidswere dissolved in minimal DCM and purified by silica chromatography(0-12% MeOH in DCM) to give benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(3-(trifluoromethyl)pyridin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(35 mg, 0.0541 mmol, 45.6%). ESI+APCI MS m/z 551.3 [M+H]⁺.

Step F:2-(4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(3-(trifluoromethyl)pyridin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:To a solution of benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(3-(trifluoromethyl)pyridin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(35.2 mg, 0.0541 mmol) in EtOH (541 μl, 0.0541 mmol) and THF (541 μl,0.0541 mmol) was added Palladium (28.8 mg, 0.0135 mmol) (Degussa Type,10 wt %, 50% H2O) and then an atmosphere of H2 was introduced via vacuumfollowed by balloon pressure. The mixture was then stirred at ambienttemperature for 1 h. The mixture was then diluted with MeOH and filteredthrough GF/F paper. The filtrate was then concentrated to provide2-(4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(3-(trifluoromethyl)pyridin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(26.4 mg, 0.0511 mmol, 94.5% yield).

Step G:2-(1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(3-(trifluoromethyl)pyridin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:To a suspension of2-(4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(3-(trifluoromethyl)pyridin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(26.4 mg, 0.0511 mmol) in CH2Cl2 (511 μl, 0.0511 mmol) at −78° C. wasadded acryloyl chloride (1022 μl, 0.102 mmol) (freshly prepared 0.1Msolution in DCM) followed by Triethylamine (14.2 μl, 0.102 mmol). Thereaction was then stirred at 0° C. for 45 minutes. LC-MS indicatedproduct formation. Reaction concentrated and purified by prep HPLC toprovide title compound2-(1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(3-(trifluoromethyl)pyridin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(EXAMPLE 375, 3 mg, 0.00526 mmol, 10.3% yield). ESI+APCI MS m/z 571.3[M+H]⁺.

Example 376

2-(1-(but-2-ynoyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile2,2,2-trifluoroacetate

Step A: tert-butyl2-chloro-4-(3-(cyanomethyl)piperazin-1-yl-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:tert-butyl2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (8.0g, 26.3 mmol), Hunig's base (22.9 ml, 132 mmol) and2-(piperazin-2-yl)acetonitrile dihydrochloride (5.21 g, 26.3 mmol) wereplaced in DMA (75 mL) and stirred at rt for 20 min. Water was added andthe mixture was extracted with EtOAc (3×100 mL). The extracts werecombined and washed with water (3×50 mL) then was dried with sodiumsulfate. The solids were filtered and the filtrate was concentrated toprovide crude tert-butyl2-chloro-4-(3-(cyanomethyl)piperazin-1-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate.ESI+APCI MS m/z 337.1 [M+H]⁺.

Step B: tert-butyl4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:tert-butyl2-chloro-4-(3-(cyanomethyl)piperazin-1-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(10.50 g, 26.73 mmol) and TEA (5.59 ml, 40.0 mmol) were placed in THF(100 mL) and was cooled to 0° C. Benzyl carbonochloridate (5.65 ml, 40.0mmol) was added and the reaction was stirred at 0° C. for 30 min. Waterwas added and the mixture was extracted with DCM (3×50 mL). The extractswere combined and concentrated. The resulting residue was purified bysilica gel (0-60% EtOAc in hex) to provide tert-butyl4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(12.94 g, 24.6 mmol, 92% yield). ESI+APCI MS m/z 527.2 [M+H]⁺.

Step C: tert-butyl4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:In a conical bottom vial, a solution of tert-butyl(S)-4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(3.28 g, 6.22 mmol) in dioxane (62.2 ml, 6.22 mmol) was sparged withargon and (S)-(1-methylpyrrolidin-2-yl)methanol (2.15 g, 18.7 mmol),Cs₂CO₃ (6.08 g, 18.7 mmol),methanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II)(0.795 g, 0.934 mmol) were sequentially added under argon and spargedfor an additional 5 min. The reaction mixture was capped and heated at100° C. for 18 hr. The reaction was cooled and water was added. Themixture was extracted with DCM (3×15 mL) and the extracts were combinedand concentrated. The resulting residue was purified by silica gel(0-12% MeOH in DCM with 0.25% NH4OH) to provide tert-butyl4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(2.65 g, 4.37 mmol, 70% yield) ESI+APCI MS m/z 606.3 [M+H]⁺.

Step D: benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:tert-butyl4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(0.61 g, 1.0 mmol) was dissolved in dichloromethane (10 ml, 1.0 mmol)and treated with hydrochloric acid (4.0 M solution in 1,4-dioxane (1 ml,5 mmol) and the reaction was stirred at room temperature for 1 hour. Thereaction was concentrated in vacuo and the material partitioned betweenEtOAc and basic water and the layers were separated. The organics werewashed with brine, dried over Na₂SO₄ and concentrated in vacuo to givebenzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.4 g, 0.8 mmol, 80% yield). ESI+APCI MS m/z 506.2 [M+H]⁺.

Step E: benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:To a vial was added cesium carbonate (193 mg, 0.59 mmol), benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(60 mg, 0.12 mmol) and Rhuphos Pd G3 (9.92 mg, 0.012 mmol), and1-bromonaphthalene (49.8 μl, 0.36 mmol). The vial was sealed and the1,4-dioxane (1187 μl, 0.12 mmol) added through a septum. Ar was bubbledthrough the mixture for 5 minutes and then the mixture was heated to 70°C. for 7 h. The reaction was cooled, filtered through qualitative paperand concentrated. The yellow solids were dissolved in minimal DCM andpurified by silica chromatography (0-12% MeOH in DCM) to provide benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(28 mg, 0.044 mmol, 37% yield) ESI+APCI MS m/z 632.4 [M+H]⁺.

Step F:2-(4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:To a solution of benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(45 mg, 0.071 mmol) in EtOH (712 μl, 0.071 mmol) and THF (712 μl, 0.071mmol) was added palladium (38 mg, 0.018 mmol) (Degussa Type, 10 wt %,50% H2O) and then an atmosphere of H2 was introduced via vacuum followedby balloon pressure. The mixture was then stirred at ambient temperaturefor 1 h. The mixture was then diluted with MeOH and filtered throughGF/F paper. The filtrate was then concentrated to provide2-(4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(30 mg, 0.060 mmol, 85% yield). ESI+APCI MS m/z 498.3 [M+H]⁺.

Step G:2-(1-(but-2-ynoyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile2,2,2-trifluoroacetate: At 0° C., to a 25 mL RBF containingN,N-dimethylformamide (603 μl, 0.060 mmol) was added2-(4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(30 mg, 0.060 mmol) and triethylamine (12.2 mg, 0.12 mmol). The reactionmixture was vigorously stirred while 2-butynoic acid (6.08 mg, 0.072mmol) was added in one portion. 1-Propanephosphonic acid cyclicanhydride (26.9 μl, 0.090 mmol) was added slowly to the stirringmixture. The reaction was allowed to stir for 2 hr at 0° C. Water wasadded and the reaction extracted with EtOAc (2×25 mL). The organiclayers were washed with saturated LiCl. NaCl, and water (10 mL eachwash). Dried and concentrated to a solid that was purified by prep HPLC(5-95% ACN:H2O, TFA) which provided title compound2-(1-(but-2-ynoyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile2,2,2-trifluoroacetate (EXAMPLE 376, 11.2 mg, 0.02 mmol, 33% yield)ESI+APCI MS m/z 564.3 [M+H]⁺.

Example 377

2-((S)-1-acryloyl-4-(2-(((S)-1-methylpiperidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A:2-((S)-4-(2-(((S)-1-methylpiperidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:To a solution of benzyl(S)-4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(0.30 g, 0.54 mmol) in dioxanes was added(S)-(1-methylpiperidin-2-yl)methanol (0.49 g, 3.8 mmol) and Cs₂CO₃ (0.53g, 1.6 mmol) and the reaction degassed with Argon for 15 minutes,followed by addition of Rhuphos Pd G3 (0.068 g, 0.081 mmol) and thereaction heated to 10° C. for overnight. The reaction was cooled andfiltered through GFF paper and the filtrate concentrated in vacuo. Theresidue was next chromatographed using 1→15% MeOH/DCM with 2% AmmoniumHydroxide as eluent to give2-((S)-4-(2-(((S)-1-methylpiperidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(0.23 g, 0.45 mmol, 83% yield). ESI+APCI MS m/z 512.3 [M+H]⁺.

Step B:2-((S)-1-acryloyl-4-(2-(((S)-1-methylpiperidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:To a solution of2-((S)-4-(2-(((S)-1-methylpiperidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(0.23 g, 0.45 mmol) in DCM (20 mL) cooled to 0° C. was addedN-ethyl-N-isopropylpropan-2-amine (0.16 ml, 0.90 mmol) followed byaddition of a solution of acryloyl chloride (0.037 ml, 0.45 mmol) (in 10mL of DCM) and the reaction stirred at 0° C. for 10 minutes. To thereaction was next added 1 mL of methanol and the reaction concentratedin vacuo. The material was next chromatographed 2× using 1→10% MeOH/DCMwith 2% NH₄OH as eluent to give a solid which was further purified byreverse prep HPLC using 5→95% ACN/water with 0.1% TFA as modifier togive title compound2-((S)-1-acryloyl-4-(2-(((S)-1-methylpiperidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(EXAMPLE 377, 0.030 g, 0.053 mmol, 12% yield). ESI+APCI MS m/z 566.3[M+H]⁺.

Example 378

2-((2S,5R)-1-acryloyl-5-methyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: 1-benzyl4-(tert-butyl)(2R,5R)-2-(hydroxymethyl)-5-methylpiperazine-1,4-dicarboxylate:Tert-butyl (2R,5R)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate(1.0 g, 4.34 mmol) was dissolved in water (50 mL) followed by additionof EtOAc (6.68 ml, 4.34 mmol) and sodium hydrogen carbonate (1.09 g,13.0 mmol) and and the reaction stirred 3 minutes. To the reaction wasadded benzyl carbonochloridate (0.648 ml, 4.56 mmol) in 1 bolus(internal temp from 19->25 C) and the reaction stirred overnight at roomtemperature. The layers were next separated and the organics washed withbrine, dried over MgSO₄ and concentrated in vacuo. The residue waschromatographed using 10→70% EtOAc/Hex as eluent to give 1-benzyl4-(tert-butyl)(2R,5R)-2-(hydroxymethyl)-5-methylpiperazine-1,4-dicarboxylate(1.2 g, 3.29 mmol, 75.8% yield). ESI+APCI MS m/z 265.2 [M+H-boc]⁺.

Step B: 1-benzyl4-(tert-butyl)(2R,5R)-5-methyl-2-(((methylsulfonyl)oxy)methyl)piperazine-1,4-dicarboxylate:To a solution of 1-benzyl 4-(tert-butyl)(2R,5R)-2-(hydroxymethyl)-5-methylpiperazine-1,4-dicarboxylate (1.2 g,3.3 mmol) in DCM cooled to 0 C was addedN-ethyl-N-isopropylpropan-2-amine (0.64 g, 4.9 mmol) and methanesulfonylchloride (0.30 ml, 3.6 mmol) and the reaction stirred at 0° C. for 2hrs. The organics were next washed with brine, dried over MgSO4 andconcentrated in vacuo. The material was next chromatographed using10→70% EtOAc/hex as eluent to give 1-benzyl4-(tert-butyl)(2R,5R)-5-methyl-2-(((methylsulfonyl)oxy)methyl)piperazine-1,4-dicarboxylate(1.3 g, 2.9 mmol, 89% yield). ESI+APCI MS m/z 343.1 [M+H-boc]⁺.

Step C: 1-benzyl 4-(tert-butyl)(2S,5R)-2-(cyanomethyl)-5-methylpiperazine-1,4-dicarboxylate: To asolution of 1-benzyl 4-(tert-butyl)(2R,5R)-5-methyl-2-(((methylsulfonyl)oxy)methyl)piperazine-1,4-dicarboxylate(1.3 g, 2.9 mmol) in DMA (20 mL) was added cyanosodium (0.29 g, 5.9mmol) and the reaction stirred 48 hrs at 55° C. The reaction was nextdiluted with basic water (220 mL) and the aq layer extracted with MTBE.The organics were next washed with water (2×50 mL), brine (50 mL), driedover MgSO₄ and concentrated in vacuo. The material was nextchromatographed using 10→50% EtOAc/hex as eluent to give 1-benzyl4-(tert-butyl)(2S,5R)-2-(cyanomethyl)-5-methylpiperazine-1,4-dicarboxylate (0.90 g,2.4 mmol, 82% yield). ESI+APCI MS m/z 274.1 [M+H-boc].

Step D: benzyl (2S,5R)-2-(cyanomethyl)-5-methylpiperazine-1-carboxylatehydrochloride: To a solution of 1-benzyl 4-(tert-butyl)(2S,5R)-2-(cyanomethyl)-5-methylpiperazine-1,4-dicarboxylate (0.90 g,2.4 mmol) in DCM was added hydrogen chloride (3.0 ml, 12 mmol) and thereaction stirred for 2 hrs at rt (added 5 more eq of HCl at 1 hr). Thereaction was next concentrated in vacuo and the material used crude inthe next reaction. ESI+APCI MS m/z 274.2 [M+H]⁺.

Step E: tert-butyl4-((2R,5S)-4-((benzyloxy)carbonyl)-5-(cyanomethyl)-2-methylpiperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:To the solid benzyl(2S,5R)-2-(cyanomethyl)-5-methylpiperazine-1-carboxylate hydrochloride(0.75 g, 2.4 mmol) and tert-butyl2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (0.74g, 2.4 mmol) was added DMA (10 mL) followed by Hunig's Base (1.3 ml, 7.3mmol) and the reaction stirred overnight at room temperature. Thereaction was next poured into water and and the aqueous layer extractedwith MTBE. The MTBE layer was washed with water, brine, dried over MgSO₄and concentrated in vacuo. The material was purified by columnchromatography using 10→70% etoac/hex as eluent to give tert-butyl4-((2R,5S)-4-((benzyloxy)carbonyl)-5-(cyanomethyl)-2-methylpiperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(0.72 g, 1.3 mmol, 55% yield). ESI+APCI MS m/z 541.3 [M+H]⁺.

Step F: benzyl(2S,5R)-4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl-2-(cyanomethyl)-5-methylpiperazine-1-carboxylate:To a solution of tert-butyl4-((2R,5S)-4-((benzyloxy)carbonyl)-5-(cyanomethyl)-2-methylpiperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(0.72 g, 1.3 mmol) in DCM (20 mL) was added hydrogen chloride (1.7 ml,6.7 mmol) (4 M in dioxanes) and the reaction stirred for 1 hour at roomtemperature. The reaction was next concentrated in vacuo and the residuepartitioned between EtOAc and basic water. The organics were separatedand washed with brine, dried over MgSO4 and concentrated in vacuo. Thematerial was used crude in the next rxn. ESI+APCI MS m/z 441.2 [M+H]⁺.

Step G: benzyl(S)-4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:To a solution of benzyl(2S,5R)-4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)-5-methylpiperazine-1-carboxylate(0.48 g, 1.1 mmol) in dioxanes (40 mL) was added 1-iodonaphthalene (1.4g, 5.4 mmol) and Cs₂CO₃ (1.1 g, 3.3 mmol) and the reaction degassed withAr for 15 minutes, followed by addition ofMethanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2-methylamino-1,1′-biphenyl-2-yl)palladium(II)(0.14 g, 0.16 mmol) and the reaction heated to 100° C. for 5 hours. Thereaction was next cooled and filtered through GFF paper and concentratedin vacuo. The material was next chromatographed using 10→70 etoac/hex aseluent to give benzyl(S)-4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(2.8 g, 5.1 mmol, 64% yield). ESI+APCI MS m/z 567.2 [M+H]⁺.

Step H:2-((2S,5R)-5-methyl-4-(2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:To a solution of benzyl(2S,5R)-4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)-5-methylpiperazine-1-carboxylate(0.48 g, 0.85 mmol) in dioxanes (40 mL) was added(S)(1-methylpyrrolidin-2-yl)methanol (0.39 g, 3.4 mmol) and Cs₂CO₃ (1.4g, 4.2 mmol) and the reaction degassed with Ar for 15 minutes followedby addition ofMethanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II)(0.11 g, 0.13 mmol) and the reaction heated to 100° C. for overnight.The reaction was next cooled and filtered through GFF paper andconcentrated in vacuo. The material was next chromatographed using 1→15%(MeOH+2% NH₄OH)/DCM with to give benzyl(2S,5R)-2-(cyanomethyl)-5-methyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.20 g, 0.31 mmol, 37% yield) and2-((2S,5R)-5-methyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(0.14 g, 0.27 mmol, 32% yield). ESI+APCI MS m/z 512.3 [M+H]⁺.

Step I:((2S,5R)-1-acryloyl-5-methyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:To a solution of2-((2S,5R)-5-methyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(0.14 g, 0.274 mmol) cooled to 0° C. was addedN-ethyl-N-isopropylpropan-2-amine (0.0982 ml, 0.547 mmol) followed byacryloyl chloride (0.0225 ml, 0.274 mmol) and the reaction stirred at 0°C. for 10 minutes. 1 mL of methanol was added to the reaction and thereaction concentrated in vacuo. The material was next purified by gilsonreverse prep 2 HPLC 2 times eluting with 5→95% ACN/water with 0.1% TFAas modifier. The combined fractions were partitioned between EtOAc andbasic water and the layers separated. The orgnanics were next washedwith brine, dried over MgSO₄ and concentrated in vacuo to give titlecompound2-((2S,5R)-1-acryloyl-5-methyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(EXAMPLE 378, 0.0118 g, 0.0209 mmol, 7.62% yield). ESI+APCI MS m/z 566.3[M+H]⁺.

Example 379

2-((S)-1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-((S)-1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:was prepared following Example 234, Steps H-J, substituting1-bromo-2-(trifluoromethyl)benzene for 1-bromonaphthalene in Step H.ESI+APCI MS m/z 570.3 [M+H]⁺.

Example 380

2-(1-acryloyl-4-(2-(((S)-1-(2-methoxyethyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-(1-acryloyl-4-(2-(((S)-1-(2-methoxyethyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:was prepared following Example 375, Steps C-G, substituting(S)-(1-(2-methoxyethyl)pyrrolidin-2-yl)methanol for(S)-(1-methylpyrrolidin-2-yl)methanol in Step C and 1-bromonaphthalenefor 4-bromo-3-(trifluoromethyl)pyridine hydrobromide in Step E. ESI+APCIMS m/z 596.3 [M+H]⁺.

Example 381

2-(1-acryloyl-4-(2-(((2S,4R)-4-methoxy-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: tert-butyl(2S,4R)-2-((4-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)-4-methoxypyrrolidine-1-carboxylate:was prepared following Example 375, Steps C-F, substituting tert-butyl(2S,4R)-2-(hydroxymethyl)-4-methoxypyrrolidine-1-carboxylate for(S)-(1-methylpyrrolidin-2-yl)methanol in Step C and 1-bromonaphthalenefor 4-bromo-3-(trifluoromethyl)pyridine hydrobromide in Step E

Step B: benzyl2-(cyanomethyl)-4-(2-(((2S,4R)-4-methoxy-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:benzyl4-(2-(((2S,4R)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(27.0 mg, 0.04 mmol, formaldehyde (15.7 μl, 0.2 mmol), Na(OAc)3BH (17.7mg, 0.08 mmol) were placed in THF (2 mL) and stirred for 2 hrs.Saturated bicarbonate was added and the mixture was extracted with 10%MeOH in DCM (3×15 mL). The extracts were combined, dried with sodiumsulfate, and concentrated to provide crude material which was used asis.

Step C: 2-(1-acryloyl2-(((2S,4R)-4-methoxy-1-methylpyrrolidin-2-yl(methoxy-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrilewas prepared following Example 375 Step F and G, substituting benzyl2-(cyanomethyl)-4-(2-(((2S,4R)-4-methoxy-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatefor benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(3-(trifluoromethyl)pyridin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatein Step F. ESI+APCI MS m/z 582.3 [M+H]⁺.

Example 382

2-((S)-1-acryloyl-4-(7-(3-fluoro-2-(trifluoromethyl)phenyl)-2-(((R)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-((S)-1-acryloyl-4-(7-(3-fluoro-2-(trifluoromethyl)phenyl)-2-(((R)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:was prepared following Example 234, Steps F-J, substituting(R)-(1-methylpyrrolidin-2-yl)methanol for(S)-(1-methylpyrrolidin-2-yl)methanol in Step F and1-bromo-3-fluoro-2-(trifluoromethyl)benzene for 1-bromonaphthalene inStep H. ESI+APCI MS m/z 588.3 [M+H]⁺.

Example 383

2-((S)-1-acryloyl-4-(7-(5-fluoro-4-(trifluoromethyl)pyridin-3-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-((S)-1-acryloyl-4-(7-(5-fluoro-4-(trifluoromethyl)pyridin-3-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:was prepared following Example 234, Steps H-J, substituting3-bromo-5-fluoro-4-(trifluoromethyl)pyridine for 1-bromonaphthalene inStep H. ESI+APCI MS m/z 589.3 [M+H]⁺.

Example 384

2-((S)-1-acryloyl-4-(2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(5-fluoro-4-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: benzyl(S)-4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:Tert-butyl(S)-4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(5.37 g, 10.2 mmol) was placed in DCM (75 mL) and was cooled to 0° C.HCl (12.7 ml, 50.9 mmol) was added and the reaction was warmed to rt andwas stirred for 2 hr. The reaction was concentrated and was brought upin DCM. Saturated bicarbonate was added and the mixture was extractedwith DCM (3×50 mL). The organic layers were combined, dried, andconcentrated to provide benzyl(S)-4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(4.33 g, 10.1 mmol, 99% yield) which was used as is.

Step B: benzyl(S)-4-(2-chloro-7-(5-fluoro-4-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl-2-(cyanomethyl)iperazine-1-carboxylate:To a vial was added cesium carbonate (2.29 g, 7.0 mmol), benzyl(S)-4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(1.00 g, 2.3 mmol),methanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II)(0.30 g, 0.35 mmol), 3-bromo-5-fluoro-4-(trifluoromethyl)pyridine (1.29g, 5.3 mmol) and 1,4-dioxane (15.6 ml, 2.3 mmol) the vial was degassedwith Ar and sealed then heated to 90° C. for 24 hr. The reaction wascooled and water and saturated NH4Cl was added and the mixture wasextracted with DCM. The organic layers were combined and concentrated.The resulting residue was purified by silica gel (5-75% EtOAc in hexane)to provide benzyl(S)-4-(2-chloro-7-(5-fluoro-4-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(634 mg, 1.1 mmol, 46% yield).

Step C: tert-butyl(2S,4R)-2-(((4-((S)-3-(cyanomethyl)piperazin-1-yl-7-(5-fluoro-4-(trifluoromethyl)pyridin-3-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)-4-fluoropyrrolidine-1-carboxylate:In a conical bottom vial, a solution of benzyl(S)-4-(2-chloro-7-(5-fluoro-4-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(634 mg, 1.07 mmol) in dioxane (10746 μl, 1.07 mmol) was sparged withargon. Tert-butyl(2S,4R)-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (942 mg,4.30 mmol), Cs₂CO₃ (1050 mg, 3.22 mmol),methanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II)(137 mg, 0.161 mmol) were sequentially added under argon and sparged foran additional 5 min. The reaction mixture was capped and heated at 100°C. for 18 hr. The reaction was cooled and water was added. The mixturewas extracted with DCM (3×20 mL) and the extracts were combined andconcentrated. The resulting residue was purified by silica gel (0-10%MeOH) to provide tert-butyl(2S,4R)-2-(((4-((S)-3-(cyanomethyl)piperazin-1-yl)-7-(5-fluoro-4-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)-4-fluoropyrrolidine-1-carboxylate(579 mg, 0.907 mmol, 84% yield).

Step D: tert-butyl(2S,4R)-2-(((4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(5-fluoro-4-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)-4-fluoropyrrolidine-1-carboxylate:Tert-butyl(2S,4R)-2-(((4-((S)-3-(cyanomethyl)piperazin-1-yl)-7-(5-fluoro-4-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)-4-fluoropyrrolidine-1-carboxylate(579 mg, 0.907 mmol), triethylamine (379 μl, 2.72 mmol) were placed inCH2Cl2 (9066 μl, 0.907 mmol) and cooled to 0° C. Acryloyl chloride (6044μl, 1.81 mmol) was added (freshly prepared 0.3M solution in DCM) and thereaction was stirred for 45 min at 0° C. Water was added and the mixturewas extracted with DCM (3×15 mL). The layers were combined andconcentrated to provide crude material that was used as is.

Step E:2-((S)-1-acryloyl-4-(7-(5-fluoro-4-(trifluoromethyl)pyridin-3-yl)-2-(((2S,4R)-4-fluoropyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:In a sealed vessel tert-butyl(2S,4R)-2-(((4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(5-fluoro-4-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)-4-fluoropyrrolidine-1-carboxylate(628 mg, 0.91 mmol) was placed in MeOH (2 mL). HCl (756 μl, 4.53 mmol)(6M aqueous) was added and the mixture was stirred at rt for Shr.Saturated bicarbonate was added slowly to bring the pH˜9. The mixturewas extracted with DCM (3×20 mL). The extracts were combined, dried,filtered and concentrated to provide crude material that was used as is.

Step E:2-((S)-acryloyl-4-(2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-ylmethoxy)-7-(5-fluoro-4-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:2-((S)-1-acryloyl-4-(7-(5-fluoro-4-(trifluoromethyl)pyridin-3-yl)-2-(((2S,4R)-4-fluoropyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(175 mg, 0.30 mmol), formaldehyde (111 μl, 1.48 mmol), Na(OAc)3BH (125mg, 0.59 mmol) and were placed in THF (2 mL) and stirred for 2 hrs.Saturated bicarbonate was added and the mixture was extracted with 10%MeOH in DCM (3×15 mL). The extracts were combined, dried with sodiumsulfate, and concentrated. The resulting residue was purified by silicagel (4-13% MeOH in DCM with 0.25% NH4OH) to provide2-((S)-1-acryloyl-4-(2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(5-fluoro-4-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(69.7 mg, 0.115 mmol, 39% yield). ESI+APCI MS m/z 607.2 [M+H]⁺.

Example 385

2-((S)-1-acryloyl-4-(7-(5-chloro-4-(trifluoromethyl)pyridin-3-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-((S)-1-acryloyl-4-(7-(5-chloro-4-(trifluoromethyl)pyridin-3-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:was prepared following Example 234, Steps H-J, substituting3-bromo-5-chloro-4-(trifluoromethyl)pyridine for 1-bromonaphthalene inStep H and THF for MeOH in Step I. ESI+APCI MS m/z 605.3 [M+H]⁺.

Example 386

2-((S)-1-acryloyl-4-(2-(((2S,4R)-4-fluoro-1-isopropylpyrrolidin-2-yl)methoxy)-7-(5-fluoro-4-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-((S)-1-acryloyl-4-(2-(((2S,4R)-4-fluoro-1-isopropylpyrrolidin-2-yl)methoxy)-7-(5-fluoro-4-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile,was prepared following the prep for Example 384, Step F, substitutingpropan-2-one for formaldehyde in step F. ESI+APCI MS m/z 635.3 [M+H]⁺.

Example 387

2-((S)-1-acryloyl-4-(7-(5-chloro-4-methylpyridin-3-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-((S)-1-acryloyl-4-(7-(5-chloro-4-methylpyridin-3-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:was prepared following Example 234, Steps H-J, substituting3-bromo-5-chloro-4-methylpyridine for 1-bromonaphthalene in Step H.ESI+APCI MS m/z 551.2 [M+H]⁺.

Example 388

2-((S)-1-acryloy-4-(7-(3-fluoro-2-methylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-((S)-1-acryloyl-4-(7-(3-fluoro-2-methylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:was prepared following Example 234, Steps H-J, substituting1-bromo-3-fluoro-2-methylbenzene for 1-bromonaphthalene in Step H.ESI+APCI MS m/z 534.3 [M+H]⁺.

Example 389

2-((S)-1-(but-2-ynoyl)-4-(7-(2,3-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: 1-benzyl 4-(tert-butyl)(R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate: To tert-butyl(R)-3-(hydroxymethyl)piperazine-1-carboxylate (76.0 g, 351 mmol) in a 3L flask was added water (500 mL) and the slurry was stirred until thematerial was completely dissolved. To this mixture was added EtOAc (541ml, 351 mmol) followed by NaHCO₃ (88.6 g, 1.05 mol) and the resultingmixture was stirred for 3 min (internal temp=20′C). To this mixture wasadded Cbz-Cl (52.5 ml, 369 mmol) over 3 minutes (internal temp from 20°C. to 25° C., off-gas seen at this point) and the reaction was stirredfor Id at rt. The reaction mixture was transferred to a separatoryfunnel and the organic layer was washed with brine, dried (MgSO₄) andconcentrated in vacuo. The residue was purified by flash chromatographyeluting with 10-70% EtOAc/hex to afford 1-benzyl 4-(tert-butyl)(R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate (114.6 g, 327.0 mmol,93% yield). ESI+APCI MS m/z 251.1 [M-Boc+H]⁺.

Step B: 1-benzyl 4-(tert-butyl)(R)-2-(((methylsulfonyl)oxy)methyl)piperazine-1,4-dicarboxylate: To asolution of 1-benzyl 4-(tert-butyl)(R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate (32 g, 91.3 mmol) inCH₂Cl₂ (457 mL, 0.2 M) cooled to 0° C. was added DIEA (24.6 ml, 137mmol) followed by methanesulfonyl chloride (7.77 ml, 100 mmol) over 1minute and the mixture was stirred at 0° C. for 1 h. The reactionmixture was transferred to a separatory funnel and washed with 1:1water/brine (500 mL). The organic layer was collected, dried (MgSO₄),and concentrated in vacuo. The residue was purified by flashchromatography eluting with 10-60% EtOAc/hex to afford 1-benzyl4-(tert-butyl)(R)-2-(((methylsulfonyl)oxy)methyl)piperazine-1,4-dicarboxylate (33 g,77.0 mmol, 84.3% yield). ESI+APCI MS m/z 329.1 [M-Boc+H]⁺.

Step C: 1-benzyl 4-(tert-butyl)(S)-2-(cyanomethyl)piperazine-1,4-dicarboxylate: To a solution of1-benzyl 4-(tert-butyl)(R)-2-(((methylsulfonyl)oxy)methyl)piperazine-1,4-dicarboxylate (12.6 g,29.4 mmol) in DMA (368 ml, 73.5 mmol) was sparged with argon. To thesolution was added sodium cyanide (3.60 g, 73.5 mmol) and the reactionstirred at 55° C. for 1 d, monitoring by HPLC (long method) to determinereaction completion. The reaction mixture was transferred to aseparatory funnel, diluted with 0.5M NaOH (800 mL) then extracted withMTBE (2×). The combined organic layers were next washed with basic water(2×200 mL), brine (100 mL), dried (MgSO₄) and concentrated in vacuo. Theresidue was purified by flash chromatography eluting with 10->600%EtOAc/hex as eluent to afford 1-benzyl 4-(tert-butyl)(S)-2-(cyanomethyl)piperazine-1,4-dicarboxylate (7.9 g, 22.0 mmol, 75%yield). ESI+APCI MS m/z 260.1 [M-Boc+H]⁺.

Step D: benzyl (S)-2-(cyanomethyl)piperazine-1-carboxylatehydrochloride: To a solution of 1-benzyl 4-(tert-butyl)(S)-2-(cyanomethyl)piperazine-1,4-dicarboxylate (20.4 g, 56.8 mmol) inDCM (50 mL) was added hydrogen chloride (99.3 ml, 397 mmol)(4.0 Msolution in dioxane) and the reaction stirred at rt for 1.5 hrs. Thereaction mixture was concentrated in vacuo and dried under vacuum togive benzyl (S)-2-(cyanomethyl)piperazine-1-carboxylate hydrochloride(16.8 g, 56.8 mmol, 100% yield) as a foam. ESI+APCI MS m/z 260.1 [M+H]⁺.

Step E: tert-butyl(S)-4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:To a solution of benzyl (S)-2-(cyanomethyl)piperazine-1-carboxylatehydrochloride (16.8 g, 56.8 mmol) in DMA (114 ml, 56.8 mmol) was addedtert-butyl2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (15.5g, 51.1 mmol) followed by DIEA (39.7 ml, 227 mmol) and the reactionmixture was stirred at RT for 1 hr. The reaction mixture was dilutedwith 1 L of water and extracted with MTBE (2×). The combined organicswere washed with water (2×200 mL), brine, dried over MgSO₄ andconcentrated in vacuo. The residue was purified by flash chromatographyeluting with 10-60% EtOAc/hex as eluent to give tert-butyl(S)-4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(22.8 g, 43.3 mmol, 76% yield). ESI+APCI MS m/z 527.2 [M+H]⁺.

Step F: tert-butyl4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl]methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate.In 250 mL heavy-wall RBF with a PTFE screw cap, a solution of tert-butyl(S)-4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(5.55 g, 10.5 mmol) in dioxane (60.2 ml, 10.5 mmol) was sparged withargon and (S)-(1-methylpyrrolidin-2-yl)methanol (3.64 g, 31.6 mmol),Cs₂CO₃ (10.3 g, 31.6 mmol), Ruphos Pd G3 (0.881 g, 1.05 mmol) weresequentially added and the resulting mixture was sparged with argon foran additional 5 min. The reaction mixture was capped and heated at 100°C. for 1 d. Upon consumption of starting material, the reaction mixturewas cooled to ambient temperature and Cbz-Cl was added as necessary toconvert Cbz-hydrolyzed product to title compound. The reaction mixturewas then partitioned between EtOAc/10% brine. The aqueous layer wasextracted with EtOAc (2×). The combined organic layers were dried(MgSO4) and concentrated. The residue was purified by flashchromatography eluting with a gradient of 1.5% MeOH/0.15% NH₄OH/DCM to11.25% MeOH/1.125% NH₄OH/DCM (Premix 15% MeOH/1.5% NH₄OH in DCM and rampfrom 10-75% of this mixture in DCM) to afford the title compound (4.51g, 7.45 mmol, 71%). ESI MS m/z 606.3 [M+H]⁺.

Step G: benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:To a solution of tert-butyl4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(7.2 g, 12 mmol) in DCM (1.0 g, 12 mmol) was added HCl (4M in dioxane,15 ml, 59 mmol). The mixture was stirred at RT for 2 h. The reactionmixture was concentrated to the bis HCl salt. The residue waspartitioned between DCM/NaHCO3 (sat) and the aqueous layer was extractedwith DCM (3×). The combined organic layers were dried and concentratedto provide the title compound 4.72 g (0.009 mmol, 79%) ESI MS m/z 506.3[M+H]⁺.

Step H: benzyl(S)-2-(cyanomethyl)-4-(7-(2,3-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl]methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:To a vial was added cesium carbonate (967 mg, 2.97 mmol), benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(500 mg, 0.989 mmol), Rhuphos Pd G3 (124 mg, 0.148 mmol),1-bromo-2,3-dimethylbenzene (915 mg, 4.94 mmol) and 1,4-dioxane (9889μl, 0.989 mmol) the vial was degassed with Ar and sealed then heated to75° C. for 24 hr. Water and saturated NH4Cl was added and the mixturewas extracted with DCM. The organic layers were combined andconcentrated. The resulting residue was purified by silica gel (0-12%MeOH in DCM w/0.25% NH4OH) to provide benzyl(S)-2-(cyanomethyl)-4-(7-(2,3-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(505 mg, 0.828 mmol, 83.7% yield). ESI MS m/z 610.4 [M+H]⁺.

Step I:2-((S)-4-(7-(2,3-dimethylphenyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl)acetonitrile:To a solution of benzyl(S)-2-(cyanomethyl)-4-(7-(2,3-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(505 mg, 0.828 mmol) in EtOH (8282 μl, 0.828 mmol) and THF (8282 μl,0.828 mmol) was added palladium (441 mg, 0.207 mmol) (Degussa Type, 10wt %, 50% H2O) and then an atmosphere of H2 was introduced via vacuumfollowed by balloon pressure. The mixture was then stirred at ambienttemperature for 2 hours. The mixture was then diluted with MeOH and THF1:1 and filtered through GF/F paper. The filtrate was then concentratedto provide crude product which was used as is. ESI MS m/z 476.3 [M+H]⁺.

Step J:2-((S)-1-but-2-ynoyl)-4-(7-(2,3-dimethylphenyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:At 0° C., to a 25 mL RBF containing N,N-dimethylformamide (4415 μl,0.4415 mmol) was added2-((S)-4-(7-(2,3-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(210 mg, 0.44 mmol) and triethylamine (122.7 μl, 0.88 mmol). Thereaction mixture was vigorously stirred while but-2-ynoic acid (44.54mg, 0.53 mmol) was added in one portion. 1-Propanephosphonic acid cyclicanhydride (197.1 μl, 0.66 mmol) was added slowly to the stirringmixture. The reaction was allowed to stir for 2 hr at 0° C. Water wasadded and the solids were filtered. The solids were purified by silicagel (5-18% MeOH in DCM with 0.25% NH4OH) to provide title compound2-((S)-1-(but-2-ynoyl)-4-(7-(2,3-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(EXAMPLE 389, 144 mg, 0.27 mmol, 60%). ESI+APCI MS m/z 542.3 [M+H]⁺.

Example 390

2-((S)-1-acryloyl-4-(2-(((2R,3S)-3-hydroxy-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: benzyl(S)-4-(2-(((2R,3S)-1-(tert-butoxycarbonyl)-3-((tert-butyldimethylsiyl)oxy)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:was prepared according to Example 400, Step C-E substituting tert-butyl(2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylatefor (S)-(1-methylpyrrolidin-2-yl)methanol in Step C.

Step B:2-((S)-1-acryloyl-4-(2-(((2R,3S)-3-hydroxypyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitriletert-butyl(2R,3S)-2-(((4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)-3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate(363 mg, 0.473 mmol) was placed in MeOH (10 mL). 6M aqeuous HCl wasadded and stirred at rt for 6 hr. The reaction was cooled to 0° C. andsaturated bicarbonate was added slowly. The mixture was extracted withDCM (3×20 ml). The extracts were combined, dried, filtered andconcentrated to provide crude material that was used as is.

Step C:2-((S)-1-acryloyl-4-(2-(((2R,3S)-3-hydroxy-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:Was prepared according to EXAMPLE 384, Step F substituting2-((S)-1-acryloyl-4-(2-(((2R,3S)-3-hydroxypyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrilefor2-((S)-1-acryloyl-4-(7-(5-fluoro-4-(trifluoromethyl)pyridin-3-yl)-2-(((2S,4R)-4-fluoropyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.ESI+APCI MS m/z 568.3 [M+H]⁺.

Example 391

2-((S)-1-(but-2-ynoyl)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-((S)-1-(but-2-ynoyl)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:Was prepared according to Example 389, Step H-J, substituting,1-bromo-8-chloronaphthalene for 1-bromo-2,3-dimethylbenzene in Step H.ESI+APCI MS m/z 598.2 [M+]⁺.

Example 392

2-((S)-1-(cyclobut-1-ene-1-carbonyl)-4-(7-(2,3-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-((S)-1-(cyclobut-1-ene-1-carbonyl)-4-(7-(2,3-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:Was prepared following Example 39 Step J, substitutingcyclobut-1-ene-1-carboxylic acid for but-2-ynoic acid. ESI+APCI MS m/z556.3 [M+H]⁺.

Example 393

2-((S)-1-acryloyl-4-(7-(3-methyl-2-(trifluoromethyl)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: benzyl(S)-2-(cyanomethyl)-4-(7-(3-methyl-2-trifluoromethyl)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate.Benzyl(S)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(150 mg, 0.22 mmol), K₂CO₃ (329 μl, 0.66 mmol),2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (82.6 mg, 0.658 mmol) andTetrakis (25.3 mg, 0.022 mmol) were placed in dioxane (731 μl, 0.22mmol) and heated to 90° C. for 18 hr. Water was added and the mixturewas extracted with 10% MeOH in DCM (3×15 mL). The extracts were combinedand concentrated. The resulting residue was purified by silica gel(2-80% MeOH in DCM with 0.25% NH4OH) to provide benzyl(S)-2-(cyanomethyl)-4-(7-(3-methyl-2-(trifluoromethyl)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrindin-4-yl)piperazine-1-carboxylate(75 mg, 0.11 mmol, 52% yield).

Step B:2-((S)-1-acryloyl-4-(7-(3-methyl-2-(trifluoromethylphenyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:Was prepared following Example 234, Step I and J substituting benzyl(S)-2-(cyanomethyl)-4-(7-(3-methyl-2-(trifluoromethyl)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatefor benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatein Step I. ESI+APCI MS m/z 584.3 [M+H]⁺.

Example 394

2-((S)-1-acryloyl-4-(7-(2,3-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-((S)-1-acryloyl-4-(7-2,3-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:was prepared following Example 234, Steps H-J, substituting1-bromo-2,3-dimethylbenzene for 1-bromonaphthalene in Step H. ESI+APCIMS m/z 530.3 [M+H]⁺.

Example 395

2-(1-acryloyl-4-(2-(((S)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: benzyl 4-(2-(((S)-1-(tert-butoxycarbonyl2-methylpyrrolidin-2-yl)methoxy7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:In a microwave tube benzyl4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(200 mg, 0.362 mmol) was dissolved in dioxane (181 μl, 0.362 mmol) andtreated with cesium carbonate (236 mg, 0.723 mmol) and (S)-tert-butyl2-(hydroxymethyl)-2-methylpyrrolidine-1-carboxylate (389 mg, 1.81 mmol),The tube was then capped and heated to 90° C. for 2 hours. The reactionwas cooled to room temperature and filtered through GF/F paper. Thefiltrate was concentrated in vacuo and chromatographed on the CombiFlasheluting with 0%-10% DCM:MeOH. All fractions containing clean productwere combined and concentrated to give benzyl4-(2-(((S)-1-(tert-butoxycarbonyl)-2-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(264 mg, 0.361 mmol, 99.7% yield). ESI+APCI MS m/z 732.4 [M+H]⁺.

Step B: benzyl2-(cyanomethyl)-4-(2-(((S)-2-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:Benzyl4-(2-(((S)-1-(tert-butoxycarbonyl)-2-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(264 mg, 0.361 mmol) was dissolved in dichloromethane (3607 μl, 0.361mmol) and treated with TFA (556 μl, 7.21 mmol). The reaction stirred atroom temperature for 1 hour. The reaction was concentrated in vacuo andtreated with saturated bicarb. The aqueous was extracted with DCM (2×)and the combined organics dried over Na₂SO₄. The organics wereconcentrated in vacuo to give benzyl2-(cyanomethyl)-4-(2-(((S)-2-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(210 mg, 0.332 mmol, 92.2% yield). ESI+APCI MS m/z 632.3 [M+H]⁺.

Step C: benzyl2-(cyanomethyl)-4-(2-(((S)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:Benzyl2-(cyanomethyl)-4-(2-(((S)-2-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(105 mg, 0.1662 mmol) was dissolved in formic acid (94.05 μl, 2.493mmol) and treated with Formaldehyde (1868 μl. 24.93 mmol). The reactionmixture stirred at 85° C. for 1 hour. The reaction was cooled to roomtemperature and treated with saturated bicarb. The aqueous was extractedwith DCM (2×). The combined organics were dried over Na₂SO₄,concentrated in vacuo and chromatographed on the CombiFlash eluting with0%-10% DCM:MeOH. All fractions containing clean product were combinedand concentrated in vacuo to give benzyl2-(cyanomethyl)-4-(2-(((S)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(75 mg, 0.1161 mmol, 69.88% yield). ESI+APCI MS m/z 646.3 [M+H]⁺.

Step D:2-(4-(2-(((S)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:A solution of benzyl2-(cyanomethyl)-4-(2-(((S)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(117 mg, 0.181 mmol) in EtOH (1812 μl, 0.181 mmol) and THF (1812 μl,0.181 mmol) was purged with N₂ for 5 minutes. To this solution was addedPalladium (96.4 mg, 0.0453 mmol) (Degussa Type, 10 wt %, 50% H₂O), andwas immediately capped and purged with N₂ for an additional 5 min. Thesolution then stirred under an atmosphere of H₂. The mixture was thendiluted with MeOH and filtered through packed celite. The filtrate wasthen concentrated in vacuo to provide2-(4-(2-(((S)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(88 mg, 0.172 mmol, 94.9% yield). ESI+APCI MS m/z 512.3 [M+H]⁺.

Step E:2-(1-acryloyl-4-(2-(((S)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:To a suspension of2-(4-(2-(((S)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(88 mg, 0.17 mmol) in dichloromethane (1720 μl, 0.17 mmol) at ambienttemperature was added Acryloyl Chloride (14 μl, 0.17 mmol) followed byHunig's base (60 μl, 0.34 mmol). The reaction was then stirred atambient temperature for 30 minutes. The reaction mixture was thenconcentrated in vacuo. The concentrate was suspended in a 60:40 mixtureof ACN:H₂O and purified on the Gilson (reverse prep HPLC), eluting with5->95% ACN/0.1% TFA in water/0.1% TFA. Fractions containing product werecombined and partitioned between saturated bicarb and DCM. The aqueouslayer was extracted with DCM two more times. The organic layers werecombined, dried over Na₂SO₄ and concentrated in vacuo to give2-(1-acryloyl-4-(2-(((S)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(14 mg, 0.025 mmol, 14% yield). ESI+APCI MS m/z 566.3 [M+H]⁺.

Example 396

2-(1-acryloyl-4-(2-(((S)-1-(cyclopropylmethyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: benzyl2-(cyanomethyl)-4-(2-(((S)-1-(cyclopropylmethyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:In a conical bottom vial, a solution of benzyl4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(200 mg, 0.362 mmol) in dioxane (3616 μl, 0.362 mmol) was sparged withArgon and (S)-(1-(cyclopropylmethyl)pyrrolidin-2-yl)methanol (168 mg,1.08 mmol), Cs₂CO₃ (353 mg, 1.08 mmol), Rhuphos Pd G3 (30.2 mg, 0.0362mmol) were sequentially added under argon and sparged for an additional5 min. The reaction mixture was capped and heated at 100° C. for 1 hour.The reaction mixture was cooled to room temperature. EtOAc was added andwashed with brine (2×). The combined organics were dried over Na₂SO₄ andconcentrated in vacuo. The concentrate was purified by flashchromatography eluting with 0-20% DCM/MeOH+2% NH₄OH. All fractionscontaining clean desired product were combined and concentrated to givebenzyl2-(cyanomethyl)-4-(2-(((S)-1-(cyclopropylmethyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(90 mg, 0.134 mmol, 37.0% yield). ESI+APCI MIS m/z 672.4 [M+H]⁺.

Step B:2-(4-(2-(((S)-1-(cyclopropylmethyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:A solution of benzyl2-(cyanomethyl)-4-(2-(((S)-1-(cyclopropylmethyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(90 mg, 0.13 mmol) in EtOH (1340 μl, 0.13 mmol) and THF (1340 μl, 0.13mmol) was purged with N₂ for 5 min. To this solution was added Palladium(36 mg, 0.033 mmol) (Degussa Type, 10 wt %, 50% H₂O), and wasimmediately capped and purged with N₂ for an additional 5 min. Thesolution then stirred under an atmosphere of H₂. The mixture was dilutedwith MeOH and filtered through packed celite. The filtrate wasconcentrated in vacuo to provide crude2-(4-(2-(((S)-1-(cyclopropylmethyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(71 mg, 0.13 mmol, 99% yield). ESI+APCI MS m/z 538.3 [M+H]⁺.

Step C:2-(1-acryloyl-4-(2-(((S)-1-(cyclopropylmethyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:To a suspension of2-(4-(2-(((S)-1-(cyclopropylmethyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(71 mg, 0.132 mmol) in dichloromethane (1320 μl, 0.132 mmol) at ambienttemperature was added Acryloyl Chloride (10.7 μl, 0.132 mmol) followedby Hunig's base (46.1 μl, 0.264 mmol). The reaction was stirred atambient temperature for 1 hour. The reaction mixture was concentrated invacuo. The concentrate was suspended in a 60:40 mixture of ACN: 1120 andpurified on the Gilson (reverse prep HPLC), eluting with 5->95% ACN/0.1%TFA in water/0.1% TFA. Fractions containing product were combined andpartitioned between saturated bicarb and DCM. The aqueous layer wasextracted with DCM two more times. The organic layers were combined,dried over Na₂SO₄ and concentrated in vacuo to give title compound2-(1-acryloyl-4-(2-(((S)-1-(cyclopropylmethyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(EXAMPLE 396, 15.7 mg, 0.0265 mmol, 20.1% yield). ESI+APCI MS m/z 592.4[M+H]⁺.

Example 397

2-(1-acryloyl-4-(2-(2-(dimethylamino)-2-methylpropoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-(1-acryloyl-4-(2-(2-(dimethylamino)-2-methylpropoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:The title compound was prepared following Example 3% substituting2-Dimethylamino-2-methyl-1-propanol for(S)-(1-(cyclopropylmethyl)pyrrolidin-2-yl)methanol in Step A. ESI+APCIMS m/z 554.4 [M+H]⁺.

Example 398

2-((2S)-2-(((4-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)pyrrolidin-1-yl)-N,N-dimethylacetamide

Step A: benzyl4-(2-(((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:In a microwave tube benzyl4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(200 mg, 0.362 mmol) was dissolved in dioxane (181 μl, 0.362 mmol) andtreated with cesium carbonate (236 mg, 0.723 mmol) andN-tert-Butoxycarbonyl-L-prolinol (364 mg, 1.81 mmol). The tube was thencapped and heated to 90° C. overnight. The reaction mixture was cooledto room temperature and filtered through GF/F paper and concentrated invacuo. The concentrate was chromatographed on the CombiFlash elutingwith 0%-10% DCM:MeOH. All fractions containing clean product werecombined and concentrated to give benzyl4-(2-(((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(225 mg, 0.313 mmol, 86.7% yield). ESI+APCI MS m/z 718.4 [M+H]⁺.

Step B: benzyl2-(cyanomethyl)-4-(7-(naphthalen-1-yl)-2-(((S)-pyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:Benzyl4-(2-(((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(225 mg, 0.313 mmol) was dissolved in dichloromethane (3134 μl, 0.313mmol) and treated with TFA (483 μl, 6.27 mmol). The reaction stirred atroom temperature for 1 hour. The reaction was concentrated in vacuo andthe organics washed with saturated bicarb. The organics were extractedwith DCM(3×). The combined organics were dried over Na₂SO₄ andconcentrated in vacuo to give benzyl2-(cyanomethyl)-4-(7-(naphthalen-1-yl)-2-(((S)-pyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(111 mg, 0.180 mmol, 57.3% yield) ESI+APCI MS m/z 618.3 [M+H]⁺.

Step C: benzyl2-(cyanomethyl)-4-(2-(((S)-1-(2-(dimethylamino)-2-oxoethyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:Benzyl2-(cyanomethyl)-4-(7-(naphthalen-1-yl)-2-(((S)-pyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(111 mg, 0.1797 mmol) was dissolved in dichloromethane (1797 μl, 0.1797mmol) and treated with N-ethyl-N-isopropylpropan-2-amine (156.9 μl,0.8984 mmol) and Chloroacetyldimethylamine (46.20 μl, 0.4492 mmol). Thereaction was stirred at room temperature for 30 minutes. 2 moreequivalences of base were added and the reaction stirred for anadditional 3 hours. The reaction was concentrated in vacuo and waschromatographed on the CombiFlash eluting with 0%-15% DCM/MeOH+0.5%NH₄OH modifier. All fractions containing clean desired product werecombined and concentrated to give benzyl2-(cyanomethyl)-4-(2-(((S)-1-(2-(dimethylamino)-2-oxoethyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(73 mg, 0.1039 mmol, 57.80% yield). ESI+APCI MS m/z 703.3 [M+H]⁺.

Step D:2-((2S)-2-(((4-(3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)pyrrolidin-1-yl)-N,N-dimethylacetamide:A solution of benzyl2-(cyanomethyl)-4-(2-(((S)-1-(2-(dimethylamino)-2-oxoethyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(73 mg, 0.10 mmol) in EtOH (1039 μl, 0.10 mmol) and THF (1039 μl, 0.10mmol) was purged with N₂ for 5 minutes. To this solution was addedPalladium (28 mg, 0.026 mmol) (Degussa Type, 10 wt %, 50% H₂O), and wasimmediately capped and purged with N₂ for an additional 5 minutes. Thesolution then stirred under an atmosphere of H₂. The mixture was thendiluted with MeOH and filtered through packed celite. The filtrate wasthen concentrated in vacuo to provide2-((2S)-2-(((4-(3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)pyrrolidin-1-yl)-N,N-dimethylacetamide(43 mg, 0.076 mmol, 73% yield). ESI+APCI MS m/z 569.3 [M+H]⁺.

Step E:2-((2S)-2-(((4-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)pyrrolidin-1-yl)-N,N-dimethylacetamide:To a suspension of2-((2S)-2-(((4-(3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)pyrrolidin-1-yl)-N,N-dimethylacetamide(43 mg, 0.0756 mmol) in dichloromethane (756 μl, 0.0756 mmol) at ambienttemperature was added Acryloyl Chloride (6.14 μl, 0.0756 mmol) followedby Hunig's base (26.4 μl, 0.151 mmol). The reaction was then stirred atambient temperature for 1 hour. The reaction mixture was concentrated invacuo, resuspended in a 60:40 mixture of ACN:H₂O and purified on theGilson (reverse prep HPLC), eluting with 5->95% ACN/0.1% TFA inwater/0.1% TFA. Fractions containing product were combined andpartitioned between saturated bicarb and DCM. The aqueous layer wasextracted with DCM two more times. The organic layers were combined,dried over Na₂SO₄ and concentrated in vacuo to give2-((2S)-2-(((4-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)pyrrolidin-1-yl)-N,N-dimethylacetamide(14.9 mg, 0.0239 mmol, 31.6% yield). ESI+APCI MS m/z 623.3 [M+H]⁺.

Example 399

2-(1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-3-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-(1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-3-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:The title compound was prepared following Example 396 substituting(3R)-(1-Methyl-pyrrolidin-3-yl)-methanol for(S)-(1-(cyclopropylmethyl)pyrrolidin-2-yl)methanol in Step A. ESI+APCIMS m/z 552.3 [M+H]⁺.

Example 400

2-((S)-1-acryloyl-4-(2-(((S)-1-ethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: benzyl(S)-4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:To a solution of tert-butyl(S)-4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(5.0 g, 9.5 mmol) in DCM (50 mL) was added hydrogen chloride (12 ml, 47mmol, 4 M solution in dioxanes) and the reaction stirred at roomtemperature for 1 hour. The reaction was next concentrated to a thickslurry and a mixture of EtOAc/water was added. The aqueous layer wasbasified with 1M NaOH and the aqueous layer extracted with EtOAc (2×).The combined organics were washed with brine, dried over MgSO₄ andconcentrated in vacuo to give benzyl(S)-4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(4.0 g, 9.4 mmol, 99% yield). ESI+APCI MS m/z 427.1 [M+H]⁺.

Step B: benzyl(S)-4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:To a solution of benzyl(S)-4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(3.4 g, 8.0 mmol) in dioxanes (40 mL) was added 1-iodonaphthalene (6.0ml, 40 mmol) and cesium carbonate (5.2 g, 16 mmol) and the reactiondegassed with Argon for 15 minutes followed by addition of Rhuphos Pd G3(1.00 g, 1.2 mmol) and the reaction heated to 100° C. for overnight. Thereaction was next filtered through GF/F paper and concentrated in vacuo.The material was next chromatographed using 10->70 EtOAc/Hexanes aseluent to give benzyl(S)-4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(2.8 g, 5.1 mmol, 64% yield). ESI+APCI MS m/z 553.2 [M+H]⁺.

Step C: benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-1-ethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:In a conical bottom vial a solution of benzyl(S)-4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(250 mg, 0.452 mmol) in dioxane (4520 μl, 0.452 mmol) was sparged withArgon for 5 minutes. (3R)-(1-Ethyl-pyrrolidin-3-yl)-methanol (175 mg,1.36 mmol), Cs₂CO₃ (442 mg, 1.36 mmol), Rhuphos Pd G3 (37.8 mg, 0.0452mmol) were sequentially added under Argon and sparged for an additional5 min. The reaction mixture was capped and heated at 100° C. for 1 hour.The reaction was cooled to room temperature and ethyl acetate was added.The organics were washed with brine (2×), dried over Na₂SO₄ andconcentrate in vacuo. The concentrate was purified by flashchromatography eluting with 0-20% (MeOH+2% NH₄OH)/DCM. All fractionscontaining clean desired product were combined and concentrated to givebenzyl(S)-2-(cyanomethyl)-4-(2-(((S)-1-ethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(118 mg, 0.183 mmol, 40.4% yield). ESI+APCI MS m/z 646.3 [M+H]⁺.

Step D:2-((S)-4-(2-(((S)-1-ethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:A solution of benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-1-ethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(237 mg, 0.367 mmol) in EtOH (3670 μl, 0.367 mmol) and THF (3670 μl,0.367 mmol) was purged with N₂ for 5 min. To this solution was addedPalladium (97.6 mg, 0.0917 mmol) (Degussa Type, 10 wt %, 50% H₂O), andwas immediately capped and purged with N₂ for an additional 5 min. Thesolution then stirred under an atmosphere of H₂. The mixture was thendiluted with MeOH and filtered through packed celite. The filtrate wasthen concentrated in vacuo to provide2-((S)-4-(2-(((S)-1-ethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(155 mg, 0.303 mmol, 82.5% yield). ESI+APCI MS m/z 512.3 [M+H]⁺.

Step E:2-((S)-1-acryloyl-4-(2-(((S)-1-ethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:To a suspension of2-((S)-4-(2-(((S)-1-ethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(226 mg, 0.442 mmol) in dichloromethane (4417 μl, 0.442 mmol) at ambienttemperature was added Acyloyl Chloride (35.9 μl, 0.442 mmol) followed byHunig's base (154 μl, 0.883 mmol). The reaction was stirred at ambienttemperature for 2 hours. The reaction mixture was concentrated in vacuoand loaded onto a 12 g RediSep Gold column and chromatographed on theCombiFlash (0%-15% DCM:MeOH+1% NH₄OH modifier). All fractions containingproduct were combined and concentrated in vacuo. The concentrate wassuspended in a 60:40 mixture of ACN:H₂O and purified on the Gilson(reverse prep HPLC), eluting with 5->95% ACN/0.1% TFA in water/0.1% TFA.Fractions containing product were combined and partitioned betweensaturated bicarb and DCM. The aqueous layer was extracted with DCM twomore times. The organic layers were combined, dried over Na₂SO₄ andconcentrated in vacuo to give title compound2-((S)-1-acryloyl-4-(2-(((S)-1-ethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(EXAMPLE 400, 136 mg, 0.240 mmol, 54.4% yield). ESI+APCI MS m/z 566.2[M+H]⁺.

Example 401

2-((S)-1-((E)-4-(dimethylamino)but-2-enoyl)-4-(2-(((S)-1-ethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A:2-((S)-1-((E)-4-(dimethylamino)but-2-enoyl)-4-(2-(((S)-1-ethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:To a solution of2-((S)-4-(2-(((S)-1-ethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(150 mg, 0.293 mmol), (2E)-4-(Dimethylamino)but-2-enoic acid (75.7 mg,0.586 mmol), DIEA (256 μl, 1.47 mmol) in DCM (2932 μl, 0.293 mmol) wasadded HATU (167 mg, 0.440 mmol) and the resulting mixture was stirred atroom temperature for 5 hours. The reaction mixture was partitionedbetween EtOAc and Brine. The aqueous was extracted with EtOAc (2×). Thecombined organics were dried over Na₂SO₄, and concentrated in vacuo. Theconcentrate was diluted in 60:40 ACN:H₂O and purified on the Gilson(reverse prep HPLC), eluting with 5->95% ACN/0.1% TFA in water/0.1% TFA.Fractions containing product were combined and partitioned betweensaturated bicarb and DCM. The aqueous layer was extracted with DCM twomore times. The organic layers were combined, dried over Na₂SO₄ andconcentrated in vacuo to give title compound2-((S)-1-((E)-4-(dimethylamino)but-2-enoyl)-4-(2-(((S)-1-ethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(EXAMPLE 401, 27.6 mg, 0.0443 mmol, 15.1% yield). ESI+APCI MS m/z 623.4[M+H]⁺.

Example 402

2-((S)-2-(((4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)pyrrolidin-1-yl)-N,N-dimethylacetamide

2-((S)-2-(((4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)pyrrolidin-1-yl)-N,N-dimethylacetamide:The title compound was prepared following Example 393 substitutingbenzyl(S)-4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylatefor benzyl4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylatein Step A. ESI+APCI MS m/z 623.3 [M+H]⁺.

Example 403

benzyl(S)-2-(cyanomethyl)-4-(2-((S)-3-(dimethylamino)pyrrolidin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

benzyl(S)-2-(cyanomethyl)-4-(2-((S)-3-(dimethylamino)pyrrolidin-1-yl-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:The title compound was prepared following Example 400 substituting(3S)-(−)-3-(Dimethylamino)Pyrrolidine for(3R)-(1-Ethyl-pyrrolidin-3-yl)-methanol in Step C. ESI+APCI MS m/z 551.3[M+]⁺.

Example 404

2-((S)-1-((E)-4-(dimethylamino)but-2-enoyl)-4-(7-(2,3-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: 2-tert-butyl4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylateIn a round bottom flask, a solution of tert-butyl(S)-4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(5 g, 9.487 mmol) in dioxane (94.87 ml, 9.487 mmol) was sparged withargon and (S)-(1-methylpyrrolidin-2-yl)methanol (3.278 g, 28.46 mmol),Cs₂CO₃ (9.273 g, 28.46 mmol),Methanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2-methylamino-1,1′-biphenyl-2-yl)palladium(II)(0.8078 g, 0.9487 mmol) were sequentially added under Argon and spargedfor an additional 5 minutes. The reaction mixture was capped and heatedat 100° C. over night. The reaction was filtered through GF/F paper andconcentrated in vacuo. The concentrate was purified on the Combi Flash(0-12% MeOH in DCM with 2% NH₄OH) to provide tert-butyl4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(5.425 g, 8.508 mmol, 89.68% yield). ESI+APCI MS m/z 606.4 [M+H]⁺.

Step B: benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:tert-butyl4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(5.4 g, 8.915 mmol) was dissolved in dichloromethane (89.15 ml, 8.915mmol) and treated with Hydrochloric Acid (4.0M solution in1,4-dioxane)(11.14 ml, 44.57 mmol). The reaction stirred at roomtemperature for 1 hour. The reaction was next diluted with more DCM and1M NaOH and the layers separated. The organics were next washed withbrine, dried over Na₂SO₄ and concentrated in vacuo to give benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(4.364 g, 8.631 mmol, 96.82% yield). ESI+APCI MS m/z 506.3 [M+H]⁺.

Step C:2-((S)-4-(7-(2,3-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:In a round bottom flask, a solution of benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(4.364 g, 8.631 mmol) in dioxane (43.15 ml, 8.631 mmol) was sparged withArgon for 5 minutes. 1-Bromo-2,3-dimethylbenzene (5.851 ml, 43.15 mmol),Cs₂CO₃ (14.06 g, 43.15 mmol), andMethanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II)(0.7348 g, 0.8631 mmol) were sequentially added under Argon and spargedfor an additional 5 min. The reaction mixture was capped and heated at100° C. ON. The reaction was cooled to room temperature. Ethyl acetatewas added and the reaction filtered through GF/F paper and concentratedin vacuo. The concentrate was purified twice via normal phasechromatography on the CombiFlash using 0-15% MeOH in DCM with 2% NH₄OHas eluent. Fractions containing desired product were collected andconcentrated in vacuo to give2-((S)-4-(7-(2,3-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(0.411 g, 0.8641 mmol, 100.1% yield). ESI+APCI MS m/z 476.3 [M+H]⁺.

Step D:2-((S)-1-((E)-4-(dimethylamino)but-2-enoyl)-4-(7-(2,3-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:To a solution of2-((S)-4-(7-(2,3-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(95 mg, 0.200 mmol), (2E)-4-(Dimethylamino)but-2-enoic acid (51.6 mg,0.399 mmol), DIEA (174 μl, 0.999 mmol) in DCM (1997 μl, 0.200 mmol) wasadded HATU (114 mg, 0.300 mmol) and the resulting mixture was stirred atroom temperature for 5 hours. The reaction mixture was washed with Brineand the aqueous layer extracted with DCM (2×). The combined organiclayers were dried over Na₂SO₄, concentrated, diluted in 60:40 ACN:H₂Oand purified on the Gilson (reverse prep HPLC), eluting with 5%-95%ACN/0.1% TFA in water/0.1% TFA. Fractions containing product werecombined and free based with saturated bicarb and the organics extractedwith DCM. The organics were dried over Na₂SO₄ and concentrated in vacuoto give2-((S)-1-((E)-4-(dimethylamino)but-2-enoyl)-4-(7-(2,3-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(38 mg, 0.0648 mmol, 32.4% yield). ESI+APCI MS m/z 587.4 [M+H]⁺.

Example 405

2-((2S)-1-acryloyl-4-(2-(3-(dimethylamino)piperidin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-((2S)-1-acryloyl-4-(2-(3-(dimethylamino)piperidin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:The title compound was prepared following Example 400 substitutingN,N-Dimethylpiperidin-3-amine for(3R)-(1-Ethyl-pyrrolidin-3-yl)-methanol in Step C. ESI+APCI MS m/z 565.4[M+H]⁺.

Example 406

2-((S)-1-acryloyl-4-(7-(2-chloro-3-fluorophenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-((S)-1-acryloyl-4-(7-(2-chloro-3-fluorophenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:The title compound was prepared following Example 234 substituting1-Bromo-2-chloro-3-fluorobenzene for 1-bromonaphthalene in Step H.ESI+APCI MS m/z 554.2 [M+H]⁺.

Example 407

2-((S)-1-acryloyl-4-(7-(2,3-difluorophenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-((S)-1-acryloyl-4-(7-(2,3-difluorophenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:The title compound was prepared following Example 234 substituting1-Bromo-2,3-difluorobenzene for 1-bromonaphthalene in Step H. ESI+APCIMS m/z 538.2 [M+H]⁺.

Example 408

2-((S)-1-acryloyl-4-(2-((((S)-1-methylpyrrolidin-2-yl)methyl)amino)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: benzyl(S)-2-(cyanomethyl)-4-(2-((((S)-1-methylpyrrolidin-2-yl)methyl)amino)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:benzyl(S)-4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(300 mg, 0.542 mmol) was dissolved in Dioxane and treated with(S)-(1-methylpyrrolidin-2-yl)methanamine (356 μl, 2.71 mmol). Thereaction was stirred at 80° C. for 3 hours. The reaction was cooled toroom temperature and partitioned between water and EtOAc. The aqueouslayer was extracted with EtOAc (2×). The combined organics were washedwith water and brine then dried over Na₂SO₄ and filtered. The filtratewas concentrated in vacuo and chromatographed on the CombiFlash elutingwith 0%-15% DCM:MeOH+2% NH₄OH to give benzyl(S)-2-(cyanomethyl)-4-(2-((((S)-1-methylpyrrolidin-2-yl)methyl)amino)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylateacetonitrile (146 mg, 0.231 mmol, 42.7% yield). ESI+APCI MS m/z 631.3[M+H]⁺. The rest of the synthesis for the title compound was done byfollowing Example 396 Steps B through C. ESI+APCI MS in/z 551.3 [M+H]⁺.

Example 409

(S)-2-(1-acryloyl-4-(7-(naphthalen-1-yl)-2-(2-(piperidin-1-yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

(S)-2-(1-acryloyl-4-(7-(naphthalen-1-yl)-2-(2-(piperidin-1-yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:The title compound was prepared following Example 400 substituting1-Piperidineethanol for (3R)-(1-Ethyl-pyrrolidin-3-yl)-methanol in StepC. ESI+APCI MS m/z 556.3 [M+H]⁺.

Example 410

2-((S)-1-acryloyl-4-(2-(((R)-1-methylpyrrolidin-3-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-((S)-1-acryloyl-4-(2-(((R)-1-methylpyrrolidin-3-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:The title compound was prepared following Example 400 substituting(R)-3-(hydoxymethyl)-1-methylpyrrolidine for(3R)-(1-Ethyl-pyrrolidin-3-yl)-methanol in Step C. ESI+APCI MS m/z 552.3[M+H]⁺.

Example 411

2-(1-acryloyl-4-(7-(3-fluoro-2-methylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-(1-acryloyl-4-(7-(3-fluoro-2-methylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:was prepared following Example 375, Steps E-G, substituting1-bromo-3-fluoro-2-methylbenzene for 4-bromo-3-(trifluoromethyl)pyridinehydrobromide in Step E. ESI+APCI MS m/z 534.3 [M+H]⁺.

Example 412

2-(1-acryloyl-4-(7-(2-fluoro-6-(trifluoromethyl)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-(1-acryloyl-4-(7-(2-fluoro-6-(trifluoromethyl)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:was prepared following Example 375 Steps E-G, substituting2-bromo-1-fluoro-3-(trifluoromethyl)benzene for4-bromo-3-(trifluoromethyl)pyridine hydrobromide in Step E. ESI+APCI MSm/z 588.3 [M+H]⁺.

Example 413

2-(1-acryloyl-4-(7-(4-fluoro-2-(trifluoromethyl)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-(1-acryloyl-(7-(4-fluoro-2-(trifluoromethyl)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:was prepared following Example 375 Steps E-G, substituting1-bromo-4-fluoro-2-(trifluoromethyl)benzene for4-bromo-3-(trifluoromethyl)pyridine hydrobromide in Step E. ESI+APCI MSm/z 588.3 [M+H]⁺.

Example 414

2-(1-acryloyl-4-(7-(3-chloro-2-trifluoromethyl)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-(1-acryloyl-4-(7-(3-chloro-2-trifluoromethyl)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:was prepared following Example 375 Steps E-G, substituting1-bromo-3-chloro-2-(trifluoromethyl)benzene for4-bromo-3-(trifluoromethyl)pyridine hydrobromide in Step E and THF forMeOH in Step F. ESI+APCI MS m/z 604.2 [M+H]⁺.

Example 415

2-(1-acryloyl-4-(7-(3-fluoro-2-(trifluoromethyl)phenyl)-2-(((2R,4S)-4-hydroxy-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: benzyl4-(2-chloro-7-(3-fluoro-2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl-2-(cyanomethyl)piperazine-1-carboxylate:To a vial was added cesium carbonate (4.01 g, 12.3 mmol), benzyl4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(1.75 g, 4.10 mmol) and Rhuphos Pd G3 (0.343 g, 0.410 mmol), and1-bromo-3-fluoro-2-(trifluoromethyl)benzene (4.98 g, 20.5 mmol). Thevial was sealed and the 1,4-dioxane (41.0 ml, 4.10 mmol) added through aseptum. Ar was bubbled through the mixture for 5 minutes and then themixture was heated to 70° C. for 7 h. The reaction was cooled, filteredthrough qualitative paper and concentrated. The yellow solids weredissolved in minimal DCM and purified by silica chromatography (0-12%MeOH in DCM) which provided benzyl4-(2-chloro-7-(3-fluoro-2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(1.3 g, 2.21 mmol, 54% yield.

Step B: benzyl4-(2-(((2R,4S)-1-(tert-butoxycarbonyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-yl)methoxy)-7-(3-fluoro-2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:A solution of benzyl4-(2-chloro-7-(3-fluoro-2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(150 mg, 0.255 mmol) in dioxane (2547 μl, 0.255 mmol) was sparged withargon and(2S,4R)-4-{[tert-Butyl(dimethyl)silyl]oxy}-2-(hydroxymethyl)pyrrolidine-1-carboxylate(211 mg, 0.637 mmol), Cs2CO3 (249 mg, 0.76 mmol), Rhuphos Pd G3 (21.3mg, 0.026 mmol) were sequentially added under argon and sparged for anadditional 5 min. The reaction mixture was capped and heated at 100° C.for 4 hr. The mixture was filtered through GF/F paper, concentrated andthe residue was dissolved in DCM and washed with water, aqueous wasseparated and extracted with DCM (3×15 mL). The extracts were combinedand concentrated and the resulting residue was purified by silica gel(0-50% EtOAc/hex 20CV, 50% EA/hex 2CV, 50-100% EA/hex 10CV) to providebenzyl4-(2-(((2R,4S)-1-(tert-butoxycarbonyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-yl)methoxy)-7-(3-fluoro-2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(95 mg, 0.107 mmol, 42% yield).

Step C: tert-butyl(2R,4S)-2-(((4-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(3-fluoro-2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate:was prepared following the prep for EXAMPLE 375, Step F and G,substituting benzyl4-(2-(((2R,4S)-1-(tert-butoxycarbonyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-yl)methoxy)-7-(3-fluoro-2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylatefor benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(3-(trifluoromethyl)pyridin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatein Step F.

Step D:2-(1-acryloyl-4-(7-(3-fluoro-2-(trifluoromethyl)phenyl)-2-(((2R,4S)-4-hydroxy-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:was prepared according to EXAMPLE 390, Step B and C, substitutingtert-butyl(2R,4S)-2-(((4-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(3-fluoro-2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylatefor tert-butyl(2R,3S)-2-(((4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)-3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylatein Step B. ESI+APCI MS m/z 604.3 [M+H]⁺.

Example 416

2-(1-acryloyl-4-(7-(3-fluoro-2-(trifluoromethyl)phenyl)-2-(((2R,4R)-4-hydroxy-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-(1-acryloyl-4-(7-(3-fluoro-2-(trifluoromethyl)phenyl)-2-(((2R,4R)-4-hydroxy-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:was prepared following Example 415, Steps B-D substituting tert-butyl(2R,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylatefor(2S,4R)-4-{[tert-Butyl(dimethyl)silyl]oxy}-2-(hydroxymethyl)pyrrolidine-1-carboxylatein Step B. ESI+APCI MS m/z 604.3 [M+H]⁺.

Example 417

2-(1-acryloyl-4-(2-(((2R,4S)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(3-fluoro-2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-(1-acryloyl-4-(2-(((2R,4S)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(3-fluoro-2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:was prepared following Example 415, Steps B-D substituting tert-butyl(2R,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate for(2S,4R)-4-{[tert-Butyl(dimethyl)silyl]oxy}-2-(hydroxymethyl)pyrrolidine-1-carboxylatein Step B. ESI+APCI MS m/z 606.2 [M+H]⁺.

Example 418

2-(1-acryloyl-4-(2-(((R)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(3-fluoro-2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-(1-acryloyl-4-(2-(((R)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(3-fluoro-2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:was prepared following Example 415, Steps B-D substituting tert-butyl(R)-2-(hydroxymethyl)-2-methylpyrrolidine-1-carboxylate for(2S,4R)-4-{[tert-Butyl(dimethyl)silyl]oxy}-2-(hydroxymethyl)pyrrolidine-1-carboxylatein Step B. ESI+APCI MS m/z 602.3 [M+H]⁺.

Example 419

2-(1-acryloyl-4-(2-(((2S,4S)-4-hydroxy-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-(1-acryloyl-4-(2-(((2S,4S)-4-hydroxy-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:was prepared following Example 415, Steps A-D substituting1-bromonaphthalene for 1-bromo-3-fluoro-2-(trifluoromethyl)benzene inStep A tert-butyl(2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylatefor(2S,4R)-4-{[tert-Butyl(dimethyl)silyl]oxy}-2-(hydroxymethyl)pyrrolidine-1-carboxylatein Step B. ESI+APCI MS m/z 568.3 [M+H]⁺.

Example 420

2-((S)-1-acryloyl-4-(7-(3-chloro-2-methylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-((S)-1-acryloyl-4-(7-(3-chloro-2-methylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.Was prepared following Example 234, Step H-J substituting1-bromo-3-chloro-2-methylbenzene for 1-bromonaphthalene in Step H andTHF for MeOH in Step 1. ESI+APCI MS m/z 550.3 [M+H]⁺.

Example 421

2-((S)-1-acryloyl-4-(7-(2,3-dichlorophenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-((S)-1-acryloyl-4-(7-(2,3-dichlorophenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:Was prepared following Example 234, Step H-J substituting1-bromo-2,3-dichlorobenzene for 1-bromonaphthalene in Step H and THF forMeOH in Step I. ESI+APCI MS m/z 570.2 [M+H]⁺.

Example 422

2-((S)-1-acryloyl-4-(7-(3-chloro-2-methoxyphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-((S)-1-acryloyl-4-(7-(3-chloro-2-methoxyphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:Was prepared following Example 234, Step H-J substituting1-bromo-3-chloro-2-methoxybenzene for 1-bromonaphthalene in Step H andTHF for MeOH in Step I. ESI+APCI MS m/z 566.2 [M+H]⁺.

Example 423

2-((S)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-(((R)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4-dimethylamino)but-2-enoyl)piperazin-2-yl)acetonitrile

Step A:2-((S)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-(((R)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:Example 234, Step F-1 substituting (R)-(1-methylpyrrolidin-2-yl)methanolfor (S)-(1-methylpyrrolidin-2-yl)methanol in Step F,1-bromo-3-chloro-2-(trifluoromethyl)benzene for 1-bromonaphthalene inStep H and THF for MeOH in Step I.

Step B:2-((S)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-(((R)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4-(dimethylamino)but-2-enoyl)piperazin-2-yl)acetonitrile:N,N′-Diisopropylethylamine (29.5 μl, 0.166 mmol) andO-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium PF6 HATU (25.2mg, 0.066 mmol) were added to a solution oftrans-4-dimethylaminocrotonic acid (6.42 mg, 0.05 mmol) and2-((S)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-(((R)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile2,2,2-trifluoroacetate (22 mg, 0.033 mmol) in dichloromethane (331 id,0.033 mmol). The reaction was stirred at rt for 18 hr. The mixture waswashed with brine, extracted with 30% iPrOH/CHCl3 (3×), combinedextracts and concentrated. The resulting residue was purified by reversephase chromatography (5-95% ACN/H₂O with 0.1% TFA) then free based usingDCM and aqueous bicarb to give title compound2-((S)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-(((R)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4-(dimethylamino)but-2-enoyl)piperazin-2-yl)acetonitrile(EXAMPLE 423, 10 mg, 0.015 mmol, 46% yield). ESI+APCI MS m/z661.3[M+H]⁺.

Example 424

2-((S)-1-acryloyl-4-(7-(4-fluoro-2,3-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-((S)-1-acryloyl-4-(7-(4-fluoro-2,3-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:Was prepared following Example 234, Step H-J substituting1-bromo-4-fluoro-2,3-dimethylbenzene for 1-bromonaphthalene in Step H.ESI+APCI MS m/z 548.3 [M+H]⁺.

Example 425

2-((S)-1-acryloyl-4-(7-(2-chloro-3-methylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-((S)-1-acryloyl-4-(7-(2-chloro-3-methylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:Was prepared following Example 234, Step H-J substituting1-bromo-2-chloro-3-methylbenzene for 1-bromonaphthalene in Step H andTHF for MeOH in Step I. ESI+APCI MS m/z 550.2 [M+H]⁺.

Example 426

2-((S)-1-acryloyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-(((2S,4R)-4-hydroxy-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: benzyl(S)-2-(cyanomethyl)-4-(2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:A mixture of tert-butyl(S)-4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(methylthio)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(741 mg, 1.38 mmol) in dichloromethane (9171 μl, 1.38 mmol) was treatedwith hydrochloric acid (1720 μl, 6.88 mmol) at 0° C. and stirred for 1 hafter warming to rt. The mixture was quenched with saturated NaHCO₃, theaqueous phase was separated and extracted with DCM (3×). The combinedextracts were dried, filtered and concentrated give benzyl(S)-2-(cyanomethyl)-4-(2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(608 mg, 1.39 mmol, 100% yield). ESI+APCI MS m/z 439.2 [M+H]⁺.

Step B: benzyl(S)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:To a vial was added cesium carbonate (1.65 g, 5.06 mmol), benzyl(S)-2-(cyanomethyl)-4-(2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.74 g, 1.69 mmol), and 1-bromo-3-chloro-2-(trifluoromethyl)benzene(0.876 g, 3.37 mmol) in 1,4-dioxane (11.2 ml, 1.69 mmol). The mixturewas purged with Ar for 10 min and treated withmethanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II)RuPhos Pd G4 (0.215 g, 0.253 mmol). The mixture was purged with Ar for10 min, the resulting mixture was heated to 100° C. for 4 hr. Thereaction was concentrated, treated with water, extracted with 30%iPrOH/CHCl3 (3×), dried, filtered and concentrated and the resultingresidue was purified by silica gel (2-16% MeOH in DCM with 0.25% NH4OH)to provide benzyl(S)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(388 mg, 0.63 mmol, 37% yield). ESI+APCI MS m/z 617.2 [M+H]⁺.

Step C: benzyl(2S)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-(methylsulfinyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:To a solution of benzyl(S)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(388 mg, 0.566 mmol) in dichloromethane (5659 μl, 0.566 mmol) was addedm-chloroperbenzoic acid (117.6 mg, 0.680 mmol) at 0° C. The mixture wasstirred at this temp for 90 min. The mixture was quenched with saturatedNa2S2O3, the aqueous layers were separated and extracted with EtOAc(3×). The extracts were combined dried, filtered and concentrated. Theresulting residue was purified by silica gel (0-100% EA/hex) to givebenzyl(2S)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-(methylsulfinyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(282 mg, 0.445 mmol, 79% yield).

Step D:((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-methylpyrrolidin-2-yl)methanol:To a suspension of methyl(2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-methylpyrrolidine-2-carboxylate(3.65 g, 13.3 mmol) in tetrahydrofuran (66.7 ml, 13.3 mmol), at 0° C.under nitrogen lithium borohydride (13.3 ml, 26.7 mmol) was addedslowly. The reaction was allowed to warm to RT and the mixture stirredat rt for 1& h. The reaction mixture was slowly quenched with saturatedNH₄Cl, diluted with water and extracted twice with EtOAc (20 mL). Thecombined organic phases were dried, filtered and concentrated andpurified by silica gel (0-80% EA/hex) to give((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-methylpyrrolidin-2-yl)methanol(1.8 g, 5.87 mmol, 44% yield).

Step E: benzyl(S)-4-(2-(((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-methylpyrrolidin-2-yl)methoxy)-7-(3-chloro-2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:To a solution of(2S,4R)-1-boc-4-(tert-butyldimethylsilyloxy)-2-(hydroxymethyl)pyrrolidine(144 mg, 0.587 mmol) and benzyl(2S)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-(methylsulfinyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate2,2,2-trifluoroacetate (258 mg, 0.294 mmol) in toluene (2935 μl, 0.294mmol) was added sodium-t-butoxide (42.3 mg, 0.440 mmol). The reactionwas stirred at rt for 1 h. The mixture was washed with water, extractedwith 30% iPrOH/CHCl3 (3×), combined extracts, dried, filtered andconcentrated. The resulting residue was purified by silica gel (0-100%EA/hex 20 CV) to give benzyl(S)-4-(2-(((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-methylpyrrolidin-2-yl)methoxy)-7-(3-chloro-2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(57 mg, 0.070 mmol, 23% yield).

Step F:2-((S)-4-(2-(((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-methylpyrrolidin-2-yl)methoxy)-7-(3-chloro-2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:To a solution of benzyl(S)-4-(2-(((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-methylpyrrolidin-2-yl)methoxy)-7-(3-chloro-2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(56 mg, 0.069 mmol) in THF (688 μl, 0.069 mmol) was added palladium (29mg, 0.028 mmol) (Degussa Type, 10 wt %, 50% H2O) and then an atmosphereof H2 was introduced via vacuum followed by balloon pressure and wasstirred for 6 hr. The mixture was then diluted with MeOH and filteredthrough GF/F paper. The filtrate was then concentrated to providedesired product which was used as is.

Step G:2-((S)-1-acryloyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-(((2S,4R)-4-hydroxy-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:was prepared according to EXAMPLE 384 Step D and E substituting2-((S)-4-(2-(((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-methylpyrrolidin-2-yl)methoxy)-7-(3-chloro-2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrilefor Tert-butyl(2S,4R)-2-(((4-((S)-3-(cyanomethyl)piperazin-1-yl)-7-(5-fluoro-4-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)-4-fluoropyrrolidine-1-carboxylatein Step D. ESI+APCI MS m/z 620.2 [M+H]⁺.

Example 427

2-((S)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4-(dimethylamino)but-2-enoyl)piperazin-2-yl)acetonitrile

2-((S)-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4-(dimethylamino)but-2-enoyl)piperazin-2-yl)acetonitrile:was prepared according to Example 234, substituting(S-1-methylpyrrolidin-2-yl)methanol for(R)-(1-methylpyrrolidin-2-yl)methanol in Step A. ESI+APCI MS m/z661.3[M+H]⁺.

Example 428

2-((S)-1-acryloyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-((S)-1-acryloyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:was prepared according to Example 234, Step H-J substituting1-bromo-3-chloro-2-(trifluoromethyl)benzene for 1-bromonaphthalene inStep H and THF for MeOH in Step I. ESI+APCI MS m/z 604.2 [M+H]⁺.

Example 429

1-(2-(methoxymethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: benzyl4-(4-(tert-butoxycarbonyl)-3-(methoxymethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:A stirred solution of tert-butyl2-(methoxymethyl)piperazine-1-carboxylate-(0.715 g, 3.10 mmol) inN,N-dimethylacetamide (3 ml, 2.96 mmol) was cooled on an ice bath andthen solid benzyl2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (1.00g 2.96 mmol) was added in small portions followed by addition of DIPEA(0.57 mL, 3.25 mmol). The resulting solution was warmed to r.t. andstirred for 1 hour. The reaction mixture was partitioned between water(15 ml) and MTBE (50 mL) and the layers separated. The organic layer waswashed with water (2*10 mL), brine (10 mL), dried over Na₂SO₄ andevaporated in vacuo and used crude in the next reaction.

Step B: benzyl4-(4-tert-butoxycarbonyl)-3-(methoxymethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:A mixture of crude benzyl4-(4-(tert-butoxycarbonyl)-3-(methoxymethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(500 mg, 0.940 mmol), (S)-1-methylpyrrolidin-2-yl)methanol (216 mg, 1.88mmol), Cs₂CO₃ (612 mg, 1.88 mmol) and dioxane (0.5 mL) was flushed withnitrogen, the vial was capped and stirred at 100° C. for 2 hours andthen at 120° C. overnight. The reaction mixture was cooled andpartitioned between EtOAc (20 mL) and water (10 mL). The organic layerwas separated and washed with water and brine (5 mL each), dried overNa₂SO₄ and evaporated in vacuo. The residue was chromatographed onsilica gel using 4 to 10% MeOH/DCM+0.2% NH₄OH as eluent to give product(197 mg, 34%). ESI+APCI MS m/z 611.4 [M+H]⁺.

Step C: tert-butyl2-(methoxymethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:A mixture of benzyl4-(4-(tert-butoxycarbonyl)-3-(methoxymethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(197 mg, 0.323 mmol), methanol (10 mL) and palladium on carbon (10 mg,5%, Degussa type E101 NO/W) was degassed and stirred under hydrogenatmosphere for 1 hour. The mixture was filtered through Celite (2 mL)and the celite washed with MeOH (3×3 mL). The combined filtrates wereevaporated in vacuo, azeotroped by evaporation with toluene, and driedunder high vacuum to give product (150 mg, 98%). ESI+APCI MS m/z 477.2[M+H]⁺.

Step D: tert-butyl2-(methoxymethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:A mixture of tert-butyl2-(methoxymethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(150 mg, 0.315 mmol), Cs₂CO₃ (308 mg, 0.944 mmol), dioxane (1 mL),1-iodonaphthalene (0.0689 ml, 0.472 mmol) andmethanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl)palladium(II)(RuPhos-Pd-G3, 0.1 eq., 26.3 mg, 0.0315 mmol) was purged with nitrogen,the flask was capped and and the reaction stirred at 70° C. overnight.The reaction mixture was cooled, partitioned between EtOAc (15 mL) andwater (5 mL) and the layers separated. The organic layer was washed withwater and brine (5 mL each), dried over Na₂SO₄ and evaporated in vacuo.The residue was chromatographed on silica gel using 4 to 10% MeOH+0.5%NH₄OH as eluent to give product (131 mg, 69%). ESI+APCI MS m/z 603.3[M+H]⁺.

Step E:1-(2-(methoxymethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one:Tert-butyl2-(methoxymethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(130 mg, 0.2157 mmol) was dissolved in 1M TFA/DCM and the solutionstirred at r.t. for 1 hour. The solution was partitioned between 2MNa₂CO₃ (5 mL) and DCM (15 mL) and the layers separated and the organiclayer concentrated in vacuo. The residue was dissolved in DCM (5 mL) andcooled to −30° C. with stirring and triethylamine (0.09018 ml, 0.6470mmol) added followed by addition of acryloyl chloride (0.03504 ml,0.4313 mmol). After 1 min at −30° C. the reaction mixture was quenchedwith NH₄OH (0.05 mL) and evaporated in vacuo and dried under highvacuum. The residue was dissolved in DCM (5 mL), filtered through acotton plug and chromatographed on silica gel using 5 to 10%MeOH/DCM+0.25% NH₄OH as eluent to give title compound (EXAMPLE 429,19.55 mg, 16%). ESI+APCI MS m/z 557.3 [M+H]⁺.

Example 430

2-((S)-1-acryloyl-4-(7-(isoquinolin-8-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: benzyl(S)-2-(cyanomethyl-4-(7-(isoquinolin-8-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:A mixture of benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(125 mg, 0.247 mmol), Cs₂CO₃ (242 mg, 0.742 mmol), 8-bromoisoquinoline(77.2 mg, 0.371 mmol) andmethanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl)palladium(II)(RuPhos-Pd-G3, 0.1 eq., 20.7 mg, 0.0247 mmol) in 2 mL of dioxane waspurged with nitrogen, the flask was capped and stirred at 80° C. for 2.5hours. The reaction mixture was cooled, partitioned between EtOAc (20mL) and water (10 mL) and the layers separated. The organic layer waswashed with water and brine (5 mL each), dried over Na₂SO₄ andevaporated in vacuo. The residue was chromatographed on silica gel using4% MeOH/DCM+0.4% NH₄OH as eluent to give product (100 mg, 64%). ESI+APCIMS m/z 633.3 [M+H]⁺.

Step B:2-((S)-1-acryloyl-4-(7-(isoquinolin-8-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:To a solution of benzyl(S)-2-(cyanomethyl)-4-(7-(isoquinolin-8-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(100 mg, 0.1580 mmol) in MeOH-THF (1:1; 3 mL) was added palladium oncarbon (30 mg, 5%, Degussa type E101 NO/W) and the mixture degassedunder vacuum and backfilled with hydrogen and the reaction stirred underhydrogen atmosphere for 2 hours. The reaction was filtered throughCelite (2 mL) and the celite washed with EtOH (3*2 mL). The combinedorganics were evaporated in vacuo The residue was dissolved in DCM (10mL) and the solution cooled with stirring to −30° C. To the solution wasadded NEt₃ (0.14 mL) followed by acryloyl chloride (0.02568 ml, 0.3161mmol) and the reaction mixture stirred at −30° C. for 1 minute. Thereaction was quenched with addition of NH₄OH (0.05 mL) and concentratedin vacuo. The residue was dissolved in DCM (5 mL), filtered through acotton plug and chromatographed on silica gel using 6 to 10%MeOH/DCM+0.6% NH₄OH as eluent to give title compound (EXAMPLE 430, 22.19mg, 25%). ESI+APCI MS m/z 553.3 [M+H]⁺.

Example 431

2-((S)-1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(phthalazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(phthalazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ylpiperazine-1-carboxylate:A mixture of benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(101 mg, 0.200 mmol), 1-chlorophthalazine (65.8 mg, 0.400 mmol) andN-ethyl-N-isopropylpropan-2-amine (0.0696 ml, 0.400 mmol) in 1,4-dioxane(0.5 ml, 0.200 mmol) was purged with nitrogen, the reaction capped andstirred at 80° C. for 16 hours. The reaction mixture was cooled,partitioned between EtOAc (20 mL) and water (5 mL) and the layersseparated. The organic layer was washed with water and brine (5 mLeach), dried over Na₂SO₄ and concentrated in vacuo. The residue waschromatographed on silica gel using 6% MeOH/DCM+0.6% NH₄OH as eluent togive product (53 mg, 42%). ESI+APCI MS m/z 634.3 [M+H]⁺.

Step B:2-((S)-1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy-7-(phthalazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:A mixture of benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(phthalazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(60 mg, 0.09467 mmol), methanol (2 ml) and palladium on carbon (20 mg,5%, Degussa type y E101 NO/W) was degassed under vacuum and backfilledwith hydrogen and the reaction stirred under hydrogen atmosphere for 4hours. The reaction was filtered through Celite (2 mL) and the celitewashed with MeOH (3×3 mL). The combined organics were evaporated invacuo. The residue was dissolved in DCM (5 mL) and cooled to −30° C.with stirring. To the solution was next added triethylamine (0.06598 ml,0.4734 mmol) followed by acryloyl chloride (0.02308 ml, 0.2840 mmol) andthe reaction stirred for 5 minutes at −30° C. The reaction was quenchedby addition of sat. NaHCO₃ (1 mL). The mixture was warmed up to r.t.,water was added (2 mL) and the layers were separated. The organics weredried over Na₂SO₄ and evaporated in vacuo and the residuechromatographed on silica gel using 4 to 10% MeOH+0.4% NH₄OH as eluentto give impure product, which was purified on the Gilson reverse prepHPCL eluting with 5 to 95% acetonitrile in water+0.1% TFA. Fractionscontaining product were partitioned between DCM and sat. Na₂CO₃ and thelayers separated. The organics were next washed with brine, dried overNa₂SO₄ and concentrated in vacuo to give title compound (EXAMPLE 431,1.1 mg, 2%). ESI+APCI MS m/z 554.2 [M+H]⁺.

Example 432

2-((S)-1-acryloyl-4-(2-(((R)-1-methylpiperidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A:2-((S)-4-(2-(((R)-1-methylpiperidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:A mixture of benzyl(S)-4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(250 mg, 0.452 mmol), (R)-(1-methylpiperidin-2-yl)methanol (175 mg, 1.36mmol) andMethanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2-methylamino-1,1′-biphenyl-2-yl)palladium(II)(19.2 mg, 0.0226 mmol) in 1,4-dioxane (2 mL) was purged with nitrogenand stirred at 80° C. overnight. The reaction mixture was cooled,partitioned between MTBE (20 mL) and water (5 mL) and the layersseparated. The organic layer was washed with water and brine (5 mLeach), dried over Na₂SO₄ and concentrated in vacuo. The residue wasdissolved in MeOH (5 mL) followed by addition of palladium on carbon (70mg, 5%, Degussa type E101 NO/W). The reaction mixture was degassed undervacuum and backfilled with hydrogen and the reaction stirred under H₂atmosphere for 1.5 hours. The reaction was filtered through Celite (2mL) and the Celite was washed with MeOH (3×3 mL) and concentrated invacuo to give product, which was used crude in the next reaction.ESI+APCI MS m/z 512.3 [M+H]⁺.

Step B:2-((S)-1-acryloyl-4-(2-(((R)-1-methylpiperidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:Crude2-((S)-4-(2-(((R)-1-methylpiperidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(292 mg, 0.57068 mmol) was dissolved in DCM (10 mL) followed by additionof triethylamine (238.63 μl, 1.7120 mmol) and the solution cooled to−30° C. To the reaction was next added acryloyl chloride (92.728 μl,1.1414 mmol) dropwise and the mixture stirred at −30° C. for 10 minutes.EtOH (0.1 mL) was next added and the reaction warmed to 0° C. Themixture was chromatographed directly on silica using 5% MeOH+0.5%NH₄OH/DCM as eluent followed by repurification of the material using thesame eluent conditions to give title compound (EXAMPLE 432, 107.47 mg,33%). ESI+APCI MS m/z 566.3 [M+H]⁺.

Example 433

1-((S)-2-(2-methoxyethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: 4-benzyl 1-(tert-butyl)(S)-2-(2-hydroxyethyl)piperazine-1,4-dicarboxylate: To a the solid(S)-tert-butyl-2-(2-hydroxyethyl)piperazine-1-carboxylate hydrochloride(500 mg, 1.874 mmol) and NaHCO₃ (629.8 mg, 7.497 mmol) were added EtOAc.and water (10 mL each) and the mixture cooled to 0° C. followed bydropwise addition of benzyl carbonochloridate (0.4013 ml, 2.811 mmol)and the reaction mixture stirred overnight while warming to roomtemperature. The layers were next separated and the organic layer washedwith water and brine (5 mL each), dried over Na₂SO₄ and concentrated invacuo. The material was next chromatographed on silica gel using 20% to40% EtOAc/hexane as eluent to give product (578 mg, 85%). ESI+APCI MSm/z 256.2 [M-Boc+H]⁺.

Step B: 4-benzyl 1-(tert-buty)(S)-2-(2-methoxyethyl)piperazine-1,4-dicarboxylate: A stirred solutionof 4-benzyl 1-(tert-butyl)(S)-2-(2-hydroxyethyl)piperazine-1,4-dicarboxylate (270 mg, 0.741 mmol)in N,N-dimethylformamide (3 ml, 0.741 mmol) under N₂ was cooled to −20°C. followed by addition of sodium hydride (44.4 mg, 1.11 mmol) in onebolus. To the reaction was next added iodomethane (0.138 ml, 2.22 mmol)and the reaction mixture was warmed to r.t. over 1 hour and continuedstirring for 1 hour at room temperature. The reaction was quenched byaddition of ice (˜5 g) and the mixture partitioned between MTBE (20 mL)and water (10 mL) and the layers separated. The organic layer was washedwith water and brine (5 mL each), dried over Na₂SO₄ and concentrated invacuo to give product which was used crude in the next reaction (252 mg,90%). ESI+APCI MS m/z 279.1 [M-Boc+H]⁺.

Step C: tert-butyl (S)-2-(2-methoxyethyl)iperazine-1-carboxylate: To amixture of 4-benzyl 1-(tert-butyl)(S)-2-(2-methoxyethyl)piperazine-1,4-dicarboxylate (252 mg, 0.666 mmol)in methanol (5 ml) was added palladium on carbon (50 mg, 5%, Degussatype E101 NO/W) and the reaction degassed under vacuum and backfilledwith hydrogen and the reaction stirred under hydrogen atmosphere for 3hours. The slurry was filtered through Celite (2 mL) and the Celitewashed with MeOH (3×3 mL). The combined organics were concentrated invacuo and dried under high vacuum to give product (140 mg, 86%).ESI+APCI MS m/z 245.2 [M+H]⁺.

Step D: benzyl(S)-4-(4-(tert-butoxycarbonyl)-3-(2-methoxyethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:A solution of crude tert-butyl(S)-2-(2-methoxyethyl)piperazine-1-carboxylate (140 mg, 0.573 mmol) andN,N-dimethylacetamide (0.5 ml, 0.573 mmol) was cooled to 0° C. andbenzyl 2,4-dichloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate(194 mg, 0.573 mmol) was added in one bolus. The reaction mixture wasstirred overnight followed by addition ofN-ethyl-N-isopropylpropan-2-amine (0.150 ml, 0.859 mmol) and thereaction stirred at room temperature for 1 hour. The reaction mixturewas partitioned between MTBE (20 mL) and sat. NaHCO₃ (5 mL) and thelayers separated. The organic layer was washed with water and brine (5mL each), dried over Na₂SO₄ and concentrated in vacuo. The residue waschromatographed on silica gel using 2% MeOH/DCM as eluent to giveproduct (190 mg, 61%).

Step E: benzyl4-((S)-4-(tert-butoxycarbonyl)-3-(2-methoxyethyl)piperazin-1-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:A mixture of benzyl(S)-4-(4-(tert-butoxycarbonyl)-3-(2-methoxyethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(190 mg, 0.348 mmol), (S)-(1-methylpyrrolidin-2-yl)methanol (120 mg,1.04 mmol), Cs₂CO₃ (340 mg, 1.04 mmol) and 1,4-dioxane (0.5 ml) under N₂atmosphere was heated to 120° C. for 20 hours. The reaction was cooled,diluted with EtOAc (3 mL), filtered through Celite and concentrated invacuo. The residue was chromatographed on silica gel using 4 to 8%MeOH/DCM+0.4% NH₄OH as eluent to give product (77 mg, 35%). ESI+APCI MSm/z 625.3 [M+H]⁺.

Step F: tert-butyl(S)-2-(2-methoxyethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:To a mixture of benzyl4-((S)-4-(tert-butoxycarbonyl)-3-(2-methoxyethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(77 mg, 0.12 mmol) in methanol (5 ml) was added palladium on carbon (20mg, 5%, Degussa type E101 NO/W) and the slurry degassed under vacuum andback filled with hydrogen and the reaction stirred under hydrogenatmosphere overnight. The slurry was filtered through Celite (2 mL) andthe celite washed with MeOH (3×3 mL). The combined organics wereconcentrated in vacuo and azeotroped with toluene (2×2 mL) to giveproduct which was used crude in the next reaction. ESI+APCI MS m/z 491.3[M+H]⁺.

Step G: tert-butyl(S)-2-(2-methoxyethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:A mixture of crude tert-butyl(S)-2-(2-methoxyethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(60 mg, 0.122 mmol), Cs₂CO₃ (120 mg, 0.367 mmol), dioxane (2 mL),1-iodonaphthalene (0.0268 ml, 0.183 mmol) (1.5 eq.) andmethanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl)palladium(II)(RuPhos-Pd-G3, 0.1 eq., 10.2 mg, 0.0122 mmol) was purged with nitrogenand the reaction capped and stirred at 80° C. overnight. The reactionmixture was cooled, partitioned between EtOAc (20 mL) and water (10 mL)and the layers separated. The organic layer was washed with water andbrine (5 mL each), dried over Na₂SO₄ and evaporated in vacuo. Theresidue was chromatographed on silica gel using 5% MeOH/DCM+0.5% NH₄OHas eluent to give product (56 mg, 74%). ESI+APCI MS m/z 617.4 [M+H]⁺.

Step H:4-((S)-3-(2-methoxyethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine:To the solid tert-butyl(S)-2-(2-methoxyethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(56 mg, 0.091 mmol) was added hydrogen chloride (0.5 ml, 2.0 mmol) andthe reaction stirred at 0° C. followed by warming to room temperaturefor 15 minutes, at which point a solid formed. The organics weredecanted and the solids partitioned between DCM (12 mL) and 2M Na₂CO₃ (1mL) and the layers separated. The organic layer was dried over K₂CO₃ andconcentrated in vacuo to give crude product. ESI+APCI MS m/z 517.3[M+H]⁺.

Step I:1-((S)-2-(2-methoxyethyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one.Crude4-((S)-3-(2-methoxyethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine(39 mg, 0.07548 mmol) was dissolved in DCM (10 mL) followed by additionof triethylamine (31.56 μl, 0.2264 mmol) and the solution cooled to −40°C. and stirred for 5 minutes followed by dropwise addition of acryloylchloride (12.26 μl, 0.1510 mmol). The reaction mixture was stirred at−30° C. for 10 minutes followed by addition of MeOH (0.05 mL). Themixture was warmed up to 0° C. and and the organics washed with 0.5MNa₂CO₃. The organic layer was evaporated in vacuo and chromatographed onsilica gel using 5% MeOH+0.5% NH₄OH in DCM as eluent to give titlecompound (EXAMPLE 433, 25.45 mg, 59%). ESI+APCI MS m/z 571.3 [M+H]⁺.

Example 434

2-((S)-1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(8-(trifluoromethyl)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: 8-(trifluoromethyl)naphthalen-1-yl trifluoromethanesulfonate: Toa stirred solution of 8-(trifluoromethyl)naphthalen-1-ol (500 mg, 2.36mmol) in DCM (10 mL) at 0° C. was addedN-ethyl-N-isopropylpropan-2-amine (616 μl, 3.53 mmol) followed bydropwise addition of trifluoromethanesulfonic anhydride (475 μl, 2.83mmol) and the reaction mixture stirred 1 hour while warming to roomtemperature. The reaction was next diluted with hexane (20 mL) and MTBE(5 mL) and the organics washed with sat. NaHCO₃, water and brine (5 mLeach), dried over Na₂SO₄ and concentrated in vacuo. The residue wasdissolved in 10% EtOAc/10% DCM in hexane and the material filteredthrough a silica gel plug. The organics were concentrated andchromatographed on silica gel using 5 to 10% EtOAc/hexane as eluent togive impure material. The solid was finally crystallized from hexane,and the solid washed with small amount of cold hexane to give product(482 mg, 59%).

Step B: benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(8-(trifluoromethyl)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:A mixture of crude benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(700 mg, 1.38 mmol), Cs₂CO₃ (1353 mg, 4.15 mmol), toluene (7 ml),methanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl)palladium(II)(RuPhos-Pd-G4, 0.1 eq., 116 mg, 0.138 mmol) and8-(trifluoromethyl)naphthalen-1-yl trifluoromethanesulfonate (715 mg,2.08 mmol) was purged with nitrogen and the reaction capped and stirredat 90° C. for 5 hours. The reaction mixture was cooled, partitionedbetween EtOAc (50 mL) and water (20 mL) and the layers separated. Theorganic layer was washed with water and brine (10 mL each), dried overNa₂SO₄ and evaporated in vacuo. The residue was chromatographed onsilica gel using 4% MeOH/DCM+0.4% NH₄OH as eluent to give product (86mg, 9%). ESI+APCI MS m/z 700.3 [M+H]⁺.

Step C:2-((S)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxyl)-7-(8-(trifluoromethyl)naphthalen-1-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.A mixture of benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(8-(trifluoromethyl)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(86 mg, 0.123 mmol), methanol (3 ml, 74.2 mmol) and palladium on carbon(30 mg, 5%, Degussa type E101 NO/W) was degassed under vacuum andbackfilled with hydrogen and the reaction stirred under H₂ atmospherefor 1 hour. The reaction was next filtered through Celite (2 mL) and theCelite washed with MeOH (3×3 mL). The combined organics wereconcentrated in vacuo to give crude product (60 mg, 86%).

Step D:2-((S)-1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(8-(trifluoromethyl)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-ylacetonitrile:2-((S)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(8-(trifluoromethyl)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(50 mg, 0.08839 mmol) was dissolved in DCM (10 mL) followed by additionof triethylamine (36.96 μl, 0.2652 mmol) and the solution cooled to −40°C. and stirred for 5 minute followed by dropwise addition of acryloylchloride (14.36 μl, 0.1768 mmol). The reaction mixture was stirred at−30° C. for 10 minutes followed by addition of 0.01 mL of acryloylchloride. MeOH (0.05 mL) was next added to reaction and the mixturewarmed to 0° C. The reaction was next washed with 0.5M Na₂CO₃ and theorganics separated. The organics were evaporated in vacuo andchromatographed on silica gel using 5% MeOH+0.5% NH₄OH in DCM as eluentto give title compound (EXAMPLE 434, 39 mg, 71%).

Example 435

2-((S)-1-acryloyl-4-(7-(2,3-dihydrobenzofuran-7-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: benzyl(S)-2-(cyanomethyl)-4-(7-(2,3-dihydrobenzofuran-7-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:A mixture of benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(200 mg, 0.396 mmol), Cs₂CO₃ (387 mg, 1.19 mmol), dioxane (0.5 mL),7-bromo-2,3-dihydrobenzofuran (118 mg, 0.593 mmol, 1.5 eq.) andmethanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II)(RuPhos-Pd-G4, 0.1 eq., 33.7 mg, 0.0396 mmol) was purged with nitrogen,the reaction was capped and stirred at 80° C. overnight. The reactionmixture was cooled, partitioned between EtOAc (20 mL) and water (10 mL)and then the layers were separated. The organic layer was washed withwater and brine (5 ml, each), dried over Na₂SO₄ and evaporated in vacuo.The residue was chromatographed on silica gel using 4% MeOH/DCM+0.4%NH₄OH as eluent to give product (97 mg, 39%). ESI+APCI MS m/z 624.3[M+H]⁺.

Step B:2-((S)-4-(7-(2,3-dihydrobenzofuran-7-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:A mixture of benzyl(S)-2-(cyanomethyl)-4-(7-(2,3-dihydrobenzofuran-7-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(97 mg, 0.16 mmol), methanol (4 ml), THF (4 mL) and palladium on carbon(30 mg, 5%, Degussa type E101 NO/W) was degassed under vacuum andbackfilled with hydrogen and the reaction stirred under hydrogenatmosphere overnight. The residue was filtered through Celite (1 mL) andthe celite was washed with MeOH (3×2 mL). The combined organics wereevaporated in vacuo to give crude product. ESI+APCI MS m/z 490.3 [M+H]⁺.

Step C:2-((S)-1-acryloyl-4-(7-(2,3-dihydrobenzofuran-7-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:A solution of2-((S)-4-(7-(2,3-dihydrobenzofuran-7-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(69 mg, 0.1409 mmol) in DCM (5 mL) was cooled to −30° C. with stirring.Triethylamine (58.93 μl, 0.4228 mmol) was added followed by addition ofacryloyl chloride (22.90 μl, 0.2818 mmol) and the reaction stirred for 5minutes at −30° C. The reaction was next quenched by addition of MeOH(0.05 mL) and the reaction warmed to room temperature. The organics werewashed with 0.5M Na₂CO₃ (4 mL), dried over K₂CO₃ and evaporated invacuo. The residue was chromatographed on silica gel in using 5%MeOH+0.5% NH₄OH as eluent to give title compound (EXAMPLE 435, 45.85 mg,60%). ESI+APCI MS m/z 544.3 [M+H]⁺.

Example 436

2-((S)-1-acryloyl-4-(7-(1-methyl-1H-indol-7-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: 7-iodo-1-methyl-1H-indole: A stirred solution of7-iodo-1H-indole (4.11 ml, 2.06 mmol) in N,N-dimethylformamide (4 ml,51.9 mmol) was cooled to −20° C. and sodium hydride (123 mg, 3.09 mmol)was added in small portions followed by addition of iodomethane (0.256ml, 4.11 mmol) and the mixture was warmed to room temperature over a 2hour period. The mixture was partitioned between MTBE (40 mL) andice-water mixture (20 mL) and the layers separated. The organic layerwas washed with water (2×20 mL), brine (10 mL), dried over Na₂SO₄ andevaporated in vacuo. The solid was washed with MTBE (1 mL). The solidwas recrystallized from MTBE to give product (0.31 g, 59%).

Step B: benzyl(S)-2-(cyanomethyl)-4-(7-(1-methyl-1H-indol-7-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:A mixture of benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(200 mg, 0.396 mmol), Cs₂CO₃ (387 mg, 1.19 mmol), dioxane (0.5 mL),7-iodo-1-methyl-1H-indole (153 mg, 0.593 mmol)(1.5 eq.) andmethanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II)(RuPhos-Pd-G4, 0.1 eq., 33.7 mg, 0.0396 mmol) was purged with nitrogenand the reaction capped and stirred at 90° C. for 5 hours then overnightat 80° C. The reaction mixture was cooled, partitioned between EtOAc (20mL) and water (10 mL) and the layers were separated. The organic layerwas washed with water and brine (5 mL each), dried over Na₂SO₄ andevaporated in vacuo. The residue was chromatographed on silica gel using4% MeOH/DCM+0.4% NH₄OH as eluent to give product (65 mg, 26%). ESI+APCI.MS m/z 635.3 [M+H]⁺.

Step C:2-((S)-4-(7-(1-methyl-1H-indol-7-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:A mixture of benzyl(S)-2-(cyanomethyl)-4-(7-(1-methyl-1H-indol-7-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(65 mg, 0.10 mmol), methanol (6 ml), and palladium on carbon (30 mg, 5%,Degussa type E101 NO/W) was degassed with vacuum and back filled withhydrogen and the mixture stirred under a hydrogen atmosphere overnight.The slurry was filtered through Celite (1 mL) and the Celite washed withMeOH (3×2 mL). The combined organics were evaporated in vacuo to givecrude product. ESI+APCI MS m/z 501.3 [M+H]⁺.

Step D:2-((S)-1-acryloyl-4-(7-(1-methyl-1H-indol-7-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:A solution of2-((S)-4-(7-(1-methyl-1H-indol-7-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(51 mg, 0.1019 mmol) in DCM (5 mL) was cooled to −30° C. with stirringfollowed by addition of triethylamine (42.60 μl, 0.3056 mmol) andacryloyl chloride (16.55 μl, 0.2037 mmol). After stirring at 5 minutesat −30° C., the reaction mixture was quenched with MeOH (0.05 mL) andwarmed to room temperature. The organics were washed with 0.5M Na₂CO₃ (4mL), dried over K₂CO₃ and evaporated in vacuo. The residue waschromatographed on silica gel using 5% MeOH+0.5% NH₄OH as eluent to givetitle compound (EXAMPLE 436, 36 mg, 64). ESI+APCI MS m/z 555.3 [M+H]⁺.

Example 437

2-((S)-1-acryloyl-4-(7-(2,3-dimethylphenyl)-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A:2-((S)-1-acryloyl-4-(7-(2,3-dimethylphenyl)-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:A solution of2-((S)-4-(7-(2,3-dimethylphenyl)-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(50 mg, 0.1013 mmol) in DCM (5 mL) was cooled to −30° C. followed byaddition of triethylamine (42.35 μl, 0.3039 mmol) and acryloyl chloride(16.46 μl, 0.2026 mmol). After stirring 5 minutes at −30° C. thereaction mixture was quenched with MeOH (0.05 mL) and warmed to roomtemperature. The organics were washed with 0.5M Na₂CO₃ (4 mL), driedover K₂CO₃ and evaporated in vacuo. The residue was chromatographed onsilica gel using 4% MeOH+0.4% NH₄OH as eluent to give title compound(EXAMPLE 437, 34 mg, 61%). ESI+APCI MS m/z 548.3 [M+H]⁺.

Example 438

2-((S)-1-((E)-4-(dimethylamino)but-2-enoyl)-4-(7-(2,3-dimethylphenyl)-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A:2-((S)-1-((E)-4-(dimethylamino)but-2-enoyl-4-(7-(2,3-dimethylphenyl)-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:To a stirred solution of2-((S)-4-(7-(2,3-dimethylphenyl)-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(50 mg, 0.1013 mmol) in DCM (1 mL) was added(2E)-4-(Dimethylamino)but-2-enoic acid (26.17 mg, 0.2026 mmol),N-ethyl-N-isopropylpropan-2-amine (0.03529 ml, 0.2026 mmol) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (57.77 mg, 0.1519 mmol) and the reaction mixturestirred at room temperature for 4 hours. Water (1 mL) was next added andthe reaction mixture stirred for 5 minutes. The mixture was partitionedbetween EtOAc (10 mL) and sat. NaHCO₃ (5 mL) and the layers separated.The organic layer was washed with NaHCO₃, brine, dried over K₂CO₃ andevaporated in vacuo. The residue was chromatographed on silica gel using5% MeOH+0.5% NH4OH as eluent to give title compound (EXAMPLE 438, 45 mg,74%). ESI+APCI MS m/z 605.3 [M+H]⁺.

Example 439

2-(4-acryloyl-1-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: tert-butyl4-(4-((benzyloxy)carbonyl-2-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:A stirred solution of 2-(piperazin-2-yl)acetonitrile (0.2 g, 1.278 mmol)in a mixture of DCM (20 mL) and iPrOH (10 mL) was cooled to −30° C. andbenzyl carbonochloridate (0.2190 ml, 1.534 mmol) was added dropwise andthe reaction stirred for 1 hour while warming to room temperature. Theorganics were evaporated under the slow flow of N₂. The residue wasdissolved in N,N-dimethylacetamide (1 ml, 1.278 mmol) followed byaddition of N-ethyl-N-isopropylpropan-2-amine (0.3340 ml, 1.917 mmol)and tert-butyl2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(0.3888 g, 1.278 mmol). The reaction mixture was heated to 70° C. for 2hours followed by stirring at room temperature for 4 days. The reactionwas partitioned between water (5 mL) and MTBE (20 mL) and the layerswere separated. The organics were washed with water and brine (5 mLeach), dried over Na₂SO₄ and evaporated in vacuo. The residue waschromatographed on silica gel using 40 to 100% EtOAc/hexane as eluent togive product (134 mg, 20%). ESI+APCI MS m/z 527.2 [M+H]⁺.

Step B: tert-butyl4-(4-(benzyloxycarbonyl)-2-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:A mixture of tert-butyl4-(4-((benzyloxy)carbonyl)-2-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(134 mg, 0.254 mmol), Cs₂CO₃ (249 mg, 0.763 mmol), methanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II)(21.6 mg, 0.0254 mmol), (S)-(1-methylpyrrolidin-2-yl)methanol (146 mg,1.27 mmol) and 1,4-dioxane (2 ml, 0.254 mmol) was purged with N₂, thereaction capped and stirred at 80° C. for 3 hours. The reaction mixturewas cooled, partitioned between EtOAc (20 mL) and water (5 mL) and thelayers were separated. The organics were washed with brine (5 mL), driedover Na₂SO₄ and evaporated in vacuo. The residue was chromatographed onsilica gel using 4% MeOH+0.4% NH4OH/DCM as eluent to give product (60mg, 39%). ESI APCI MS m/z 606.3 [M+H]⁺.

Step C: benzyl3-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:Neat (tert-butyl4-(4-((benzyloxy)carbonyl)-2-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(60 mg, 0.09905 mmol)) was diluted with DCM (0.2 mL). The reaction wascooled to 0° C. and 4M HCl in dioxane (0.50 mL, 20 eq) was added withstirring. The reaction mixture was warmed to room temperature and leftin a fridge overnight, at which point a solid precipitated. The liquidphase was decanted and the solid partitioned between DCM (10 mL) and 2MNa₂CO₃ (0.5 mL) and the layers were separated. The organics were driedover K₂CO₃ and evaporated under N₂ flow. The product was used crude inthe next reaction.

Step D: benzyl3-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:A mixture of crude benzyl3-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(50 mg, 0.0989 mmol), C₂CO₃ (96.7 mg, 0.297 mmol), dioxane (0.5 mL),1-iodonaphthalene (37.7 mg, 0.148 mmol, 1.5 eq.) andmethanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II)(RuPhos-Pd-G4, 0.1 eq., 8.42 mg, 0.00989 mmol) was purged with nitrogenand the reaction capped and stirred at 80° C. for 2 hours. The reactionmixture was cooled and partitioned between EtOAc (20 mL) and water (5mL) and the layers separated. The organics were washed with water andbrine (5 mL each), dried over Na₂SO₄ and evaporated in vacuo. Theresidue was chromatographed on silica using 4% MeOH/DCM+0.4% NH₄OH aseluent to give impure product, which was purified by reversed prep HPLCchromatography eluting with 5 to 95% MeCN/water+0.1% TFA (first elutedcompound). The target fractions were diluted with 2M Na₂CO₃ and theaqueous later extracted with DCM (3×20 mL). The combined extracts werewashed with brine (15 mL), dried over K₂CO₃ and evaporated in vacuo toafford product (26 mg, 42%). ESI+APCI MS m/z 632.3 [M+H]⁺.

Step E:2-(1-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:A mixture of benzyl3-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(26 mg, 0.041 mmol), methanol (2 ml), and palladium on carbon (10 mg,5%, Degussa type E101 NO/W) was degassed under vacuum and backfilledwith hydrogen and the reaction stirred under a hydrogen atmosphere for1.5 hour. The reaction was filtered through Celite (2 mL) and the Celitewashed with MeOH (3×3 mL). The combined organics were evaporated invacuo to give product which was used crude in the next reaction.ESI+APCI MS m/z 498.3 [M+H]⁺.

Step F:2-(4-acryloyl-1-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:A solution of2-(1-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(15 mg, 0.03014 mmol) in DCM (5 mL) was cooled to −30° C. with stirringfollowed by addition of triethylamine (12.60 μl, 0.09043 mmol) andacryloyl chloride (4.898 μl, 0.06028 mmol). Ater stirring 5 minutes at−30° C., the reaction mixture was quenched by addition of MeOH (0.05 mL)and warmed up to room temperature. The organics were washed with 0.5MNa₂CO₃ (4 mL), dried over Na₂CO₃ and evaporated in vacuo. The residuewas chromatographed on silica gel using 4% MeOH+0.4% NH₄OH as eluent togive title compound (EXAMPLE 439, 8.43 mg, 51%). ESI+APCI MS m/z 552.2[M+H]⁺.

Example 440

2-((S)-1-acryloyl-4-(2-(((2R,3R)-3-fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: (2R,3R)-3-fluoropyrrolidine-2-carboxylic acid: To the solid (2R,3R)-1-Boc-3-fluoropyrrolidine-carboxylic acid (400 mg, 1.71 mmol) wasadded 4M hydrogen chloride (2144 μl, 8.57 mmol) dropwise and thereaction mixture stirred at room temperature for 1.5 hours. The reactionmixture was evaporated in vacuo followed by addition of solid NaHCO₃(173 mg, 2.06 mmol) and methanol (1715 μl, 1.71 mmol) and the suspensionstirred at room temperature overnight. To the mixture was added anadditional portion of MeOH (10 mL) and the reaction mixture stirred for30 minutes and was sonicated until full dispersion of semi-solids wasachieved. This slurry was used crude in the next reaction.

Step B: (2R,3R)-3-fluoro-1-methylpyrrolidine-2-carboxylic acid: To astirred suspension of crude (2R,3R)-3-fluoropyrrolidine-2-carboxylicacid (228 mg, 1.71 mmol) in MeOH (12 mL) was added palladium on carbon(30 mg, 5%, Degussa type E101 NO/W) followed by addition of aqueousformaldehyde (159 μl, 2.14 mmol) and the reaction mixture was degassedwith hydrogen and stirred under hydrogen overnight. The reaction mixturewas filtered through Celite and the Celite was washed with MeOH (3×2mL). The combined organics were evaporated in vacuo. The semi-solid wastaken up in dioxan and evaporated under N₂ over weekend. The product wasused crude in the next reaction.

Step C: ((2R,3R)-3-fluoro-1-methylpyrrolidin-2-yl)methanol: A stirredsuspension of crude 1-Boc-2-(S)-Pyrrolidinedicarboxylic acid,3-(R)-fluoro-(252 mg, 1.71 mmol) in THF under nitrogen was cooled on to0° C. followed by dropwise addition of 2.4M lithium aluminium hydride(0.999 ml, 2.40 mmol) and the reaction stirred for 30 minutes whilewarming to room temperature. The reaction was sonicated followed byaddition of another portion of lithium aluminium hydride in THF (0.999ml, 2.40 mmol) and the reaction mixture was stirred at room temperature.The slurry was cooled on to 0° C. and quenched with successive additionof water (0.18 mL), 15% NaOH (0.18 mL) and water (0.54 mL). The slurrywas diluted with ether (20 mL) and the precipitate separated. Thereaction mixture was filtered through Celite and the Celite washed withether (3×3 mL). To the combined organics was added 4M HCl/dioxane (0.45mL, 1.1 eq.). The mixture turned from a colorless suspension into areddish precipitate. The supernatant solution was evaporated in vacuo.The residual red solid was extracted with a minimal amount of water,filtered through a cotton plug and the cotton plug was washed with asmall amount of water. The combined water solution was saturated withKOH and extracted with ether (3×7 mL). The combined extracts were driedover NaOH and evaporated partially under nitrogen to give product as asolution in ether (340 mg as 40% solution in ether, 60%)

Step D: benzyl(S)-2-(cyanomethyl)-4-(2-(((2R,3R)-3-fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:A mixture of benzyl(S)-4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(150 mg, 0.2712 mmol), Cs₂CO₃ (265.1 mg, 0.8137 mmol), 1,4-dioxane (1ml),methanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II)(23.09 mg, 0.02712 mmol) and RuPhos (9.492 mg, 0.02034 mmol) wasdegassed with nitrogen and stirred at 70° C. for 1.5 hours. The reactionmixture was cooled and partitioned between EtOAc (20 mL) and water (5mL) and the layers were separated. The organics were washed with waterand brine (5 mL each), dried over Na₂SO₄ and evaporated in vacuo. Theresidue was chromatographed on silica gel using 3% MeOH+0.3% NH₄OH inDCM as eluent to give product (108 mg, 61%). ESI+APCI MS m/z 650.3[M+H]⁺.

Step E:2-((S)-4-(2-(((2R,3R)-3-fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-2-yl)acetonitrile:A mixture of benzyl(S)-2-(cyanomethyl)-4-(2-(((2R,3R)-3-fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(108 mg, 0.166 mmol), methanol (5 ml), and palladium on carbon (35 mg,5%, Degussa type E101 NO/W) was degassed under vacuum and backfilledwith hydrogen and the reaction stirred under hydrogen atmosphere for 1.5hours. The reaction mixture was filtered through Celite (2 mL) and thecelite was washed with MeOH (3×3 mL). The combined organics wereevaporated in vacuo to give the crude product which was used in the nextreaction.

Step F:2-((S)-1-acryloyl-4-(2-(((2R,3R)-3-fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-2-yl)acetonitrile:A solution of2-((S)-4-(2-(((2R,3R)-3-fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(78 mg, 0.1513 mmol) in DCM (5 mL) was cooled to −30° C. followed byaddition of triethylamine (63.25 μl, 0.4538 mmol) and acryloyl chloride(24.58 μl, 0.3025 mmol). After stirring 5 minutes at −30° C., thereaction mixture was quenched with MeOH (0.05 mL) and warmed to roomtemperature. The mixture was washed with 0.5M Na₂CO₃ (4 mL), dried overNa₂CO₃ and evaporated in vacuo. The residue was chromatographed onsilica gel using 4% to 10% MeOH eluent to give title compound (EXAMPLE440, 63 mg, 73%). ESI+APCI MS m/z 570.3 [M+H]⁺.

Example 441

2-((S)-1-acryloyl-4-(2-(((R)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: tert-butyl4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((R)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate.A mixture of tert-butyl(S)-4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(500 mg, 0.949 mmol), (D)-(R)-(1-methylpyrrolidin-2-yl)methanol (328 mg,2.85 mmol) (3 eq.), Cs₂CO₃ (927 mg, 2.85 mmol), dioxane (1 mL) andmethanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl)palladium(II)(RuPhos-Pd-G3, 0.1 eq., 79.3 mg, 0.0949 mmol) was purged with nitrogenand the reaction was capped and stirred at 70° C. for 5 hours. Thereaction mixture was cooled, partitioned between EtOAc (20 mL) and water(10 mL) and the layers were separated. The organics were washed withwater and brine (5 mL each), dried over Na₂SO₄ and evaporated in vacuo.The residue was chromatographed on silica gel using 4 to 10% MeOH+0.5%NH₄OH as eluent to give product (150 mg, 26%). ESI+APCI MS m/z 606.3[M+H]⁺.

Step B: benzyl(S)-2-(cyanomethyl)-4-(2-(((R)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:A solution of tert-butyl4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((R)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(296 mg, 0.489 mmol) in DCM (2.5 mL) was cooled on dry ice followed byaddition of 4M HCl in dioxane (1.2 mL) and the reaction stirred for 3hours while warming to room temperature, at which point a precipitateformed. The liquid layer was decanted and the precipitate was washedwith DCM (2 mL). The solid was then stirred with a mixture of DCM (20mL) and 2M Na₂CO₃ (3 mL) for 1 hour. The layers were separated and theorganics was dried over Na₂CO₃, filtered and evaporated in vacuo. Thematerial was used crude in the next reaction. ESI+APCI MS m/z 506.3[M+H]⁺.

Step C: benzyl(S)-2-(cyanomethyl)-4-(2-(((R)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:A mixture of crude benzyl(S)-2-(cyanomethyl)-4-(2-(((R)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(247 mg, 0.489 mmol), Cs₂CO₃ (477 mg, 1.47 mmol), dioxane (2 mL),1-iodonaphthalene (107 μl, 0.733 mmol, 1.5 eq.) andmethanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl)palladium(II)(RuPhos-Pd-G3, 0.1 eq., 40.9 mg, 0.0489 mmol) was purged with nitrogenand the reaction was capped and stirred at 80° C. overnight. Thereaction mixture was cooled, partitioned between EtOAc (20 mL) and water(10 mL) and the layers separated. The organics were washed with waterand brine (5 mL each), dried over Na₂SO₄ and evaporated in vacuo. Theresidue was chromatographed on silica gel using 5% MeOH/DCM+0.25% NH₄OHas eluent to give product (216 mg, 70%). ESI+APCI MS m/z 632.3 [M+H]⁺.

Step D:2-((S)-1-acryloyl-4-(2-(((R)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:To a stirred solution of benzyl(S)-2-(cyanomethyl)-4-(2-(((R)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(216 mg, 0.3419 mmol) in MeOH-THF (1:1, 3 mL) was added palladium oncarbon (50 mg, 5%, Degussa type E101 NO/W) and the mixture was degassedunder vacuum, backfilled with hydrogen and the reaction stirred underhydrogen atmosphere for 4 hours. The reaction mixture was filteredthrough Celite (2 mL) and the celite washed with EtOH (3×2 mL). Thecombined organics were evaporated in vacuo and the residue dissolved inDCM (10 mL). The solution was cooled with stirring to −30° C. followedby addition of NEt₃ (0.28 mL, 1.71 mmol) acryloyl chloride (0.08333 ml,1.026 mmol) and the reaction stirred at −30° C. for 1 minute. Thereaction was quenched with addition of NH₄OH (0.05 mL) and warmed toroom temperature. The solution was evaporated in vacuo. The residue wasdissolved in DCM (10 mL), filtered through a cotton plug andchromatographed on silica gel using 5 to 10% MeOH+0.25% NH₄OH in DCM aseluent to give title compound (EXAMPLE 441, 109 mg, 58%). ESI+APCI MSm/z 552.3 [M+H]⁺.

Example 442

2-((S)-1-acryloyl-4-(7-(indolizin-5-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: 5-iodoindolizine: To a stirred solution of indolizine (5.69 ml,1.71 mmol) and N1,N1,N2,N2-tetramethylethane-1,2-diamine (0.282 ml, 1.88mmol) in anhydrous tetrahydrofuran (5.7 ml, 1.71 mmol) cooled to −80° C.was added a solution of butyllithium (120 mg, 1.88 mmol) dropwise. Thereaction mixture was warmed to −20° C. and kept at −20° C. for 2 hours.The mixture was cooled to −80° C. and a solution of iodine (433 mg, 1.71mmol) in dry THF (3 mL) was added. The reaction mixture was warmed toroom temperature and treated with a saturated solution of ammoniumchloride. The organic layer was separated and the aqueous layer wasextracted with hexane. The combined organics were dried over anhydrousNa₂SO₄ and concentrated in vacuo. The crude product was purified bycolumn chromatography on silica gel using hexane as eluent to giveproduct (216 mg).

Step B: benzyl(S)-2-(cyanomethyl)-4-(7-(indolizin-5-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:A mixture of crude benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(100 mg, 0.198 mmol), Cs₂CO₃ (193 mg, 0.593 mmol), dioxane (0.5 mL),5-iodoindolizine (72.1 mg, 0.297 mmol) (1.5 eq.) andmethanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II)(RuPhos-Pd-G4, 0.1 eq., 16.8 mg, 0.0198 mmol) was purged with nitrogenand the reaction was capped and stirred at 80° C. for 4 hours. Thereaction mixture was cooled, partitioned between EtOAc (20 mL) and water(10 mL) and the layers were separated. The organics were washed withwater and brine (5 mL each), dried over Na₂SO₄ and evaporated in vacuo.The residue was chromatographed on silica gel using 4% MeOH/DCM+0.4%NH₄OH as eluent to give product (74 mg, 60%). ESI+APCI MS m/z 621.3[M+H]⁺.

Step C:2-((S)-4-(7-(indolizin-5-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:A mixture of benzyl(S)-2-(cyanomethyl)-4-(7-(indolizin-5-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(74 mg, 0.12 mmol), methanol (5 ml) and palladium on carbon (20 mg, 5%,Degussa type E101 NO/W) was degassed under vacuum and backfilled withhydrogen and the reaction was stirred under a hydrogen atmosphere for 2hours. The slurry was filtered through Celite (1 mL) and the Celite waswashed with MeOH (3×2 mL). The combined organics were evaporated invacuo to give product which was used crude in the next reaction.ESI+APCI MS m/z 487.3 [M+H]⁺.

Step D:2-((S)-1-acryloyl-4-(7-(indolizin-5-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:A solution of2-((S)-4-(7-(indolizin-5-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(50 mg, 0.1027 mmol) in DCM (5 mL) was cooled to −30° C. followed byaddition of triethylamine (42.96 μl, 0.3082 mmol) and acryloyl chloride(16.70 μl, 0.2055 mmol). After stirring 5 minutes at −30° C. thereaction mixture was quenched with sat NaHCO₃ (1 mL) and warmed to roomtemperature followed by addition of water (2 mL). The layers wereseparated and the organics were dried over Na₂SO₄ and evaporated invacuo. The residue was chromatographed on silica gel using 4% MeOH+0.4%NH₄OH as eluent to give title compound (EXAMPLE 442, 33 mg, 59%).ESI+APCI MS m/z 571.3 [M+H]⁺.

Example 443

2-(1-Acryloyl-4-(2-(((R)-4-methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: tert-Butyl(2R)-2-(((4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)morpholine-4-carboxylate:Prepared according to the procedure of Example 375 Step C, substitutingbenzyl4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(65 mg, 0.118 mmol) and (R)—N-Boc-2-hydroxymethylmorpholine (76.6 mg,0.353 mmol), purifying by flash chromatography eluting with 25-100%hex/EtOAc to afford tert-butyl(2R)-2-(((4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)morpholine-4-carboxylate(49 rag, 00668 mmol, 56.8% yield). ESI+ MS m/z 734.3 (100%) [M+H]⁺.

Step B: Benzyl2-(cyanomethyl)-4-(2-(((R)-morpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatehydrochloride: Prepared according to the procedure of Example 375 StepD, substituting tert-butyl(2R)-2-(((4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)morpholine-4-carboxylate(49 mg, 0.067 mmol) to afford benzyl2-(cyanomethyl)-4-(2-(((R)-morpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatehydrochloride (45 mg, 0.067 mmol, 100%). ESI+ MS m/z 634.3 (100%)[M+H]⁺.

Step C: Benzyl2-(cyanomethyl)-4-(2-(((R)-4-methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate.To a solution of benzyl2-(cyanomethyl)-4-(2-(((R)-morpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatehydrochloride (45 mg, 0.067 mmol), formaldehyde (54 mg, 0.67 mmol) (37wt % in MeOH/water) in DCM (671 μl, 0.067 mmol) and THF (671 μl, 0.067mmol) was added NaBH(OAc)₃ (142 mg, 0.67 mmol) and the resulting mixturewas stirred at RT for 15 m. The reaction mixture was partitioned betweenethyl acetate and 1N NaOH. The aqueous layer was extracted with ethylacetate (1×). The combined organic layers were dried (MgSO₄) andconcentrated to give a residue that was purified by flash eluting with agradient of 25-50% of a 10% MeOH/1% NH4OH/DCM mixture in DCM. Theproduct-containing fractions were concentrated to afford benzyl2-(cyanomethyl)-4-(2-(((R)-4-methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(22 mg, 0.034 mmol, 51%). ESI+ MS m/z 648.3 (100%) [M+H]⁺.

Step D:2-(4-(2-(((R)-4-Methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.Prepared according to the procedure of Example 375 Step F, substitutingbenzyl2-(cyanomethyl)-4-(2-(((R)-4-methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(22 mg, 0.034 mmol) to afford2-(4-(2-(((R)-4-methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(15.9 mg, 0.031 mmol, 91%). ESI+ MS m/z 514.3 (100%) [M+H]⁺.

Step E:2-(1-Acryloyl-4-(2-(((R)-4-methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.Prepared according to the procedure of Example 375 Step G, substituting2-(4-(2-(((R)-4-methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(16 mg, 0.031 mmol) to afford title compound2-(1-acryloyl-4-(2-(((R)-4-methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(EXAMPLE 443, 8.0 mg, 0.014 mmol, 46%). ESI+MS m/z 568.3 (100%) [M+H]⁺.

Example 444

2-(1-Acryloyl-4-(2-(((S)-4-methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: tert-Butyl(2S)-2-(((4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)morpholine-4-carboxylate:Prepared according to the procedure of Example 375 Step C, substitutingbenzyl4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(65 mg, 0.118 mmol) and tert-butyl(S)-2-(hydroxymethyl)morpholine-4-carboxylate (76.6 mg, 0.353 mmol),purifying by flash chromatography eluting with 25-100% hex/EtOAc toafford tert-butyl(2S)-2-(((4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)morpholine-4-carboxylate(43 mg, 0.059 mmol, 49.9% yield). ESI+ MS m/z 734.3 (100%) [M+H]⁺.

Step B: Benzyl2-(cyanomethyl)-4-(2-(((S)-morpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatehydrochloride: Prepared according to the procedure of Example 375 StepD, substituting tert-butyl(2S)-2-(((4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)morpholine-4-carboxylate(43 mg, 0.059 mmol) to afford benzyl2-(cyanomethyl)-4-(2-(((S)-morpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatehydrochloride (39 mg, 0.058 mmol, 100%). ESI+ MS m/z 634.3 (100%)[M+H]⁺.

Step C: Benzyl2-(cyanomethyl)-4-(2-(((S)-4-methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate.Prepared according to the procedure from Example 443 step C,substituting benzyl2-(cyanomethyl)-4-(2-(((S)-morpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatehydrochloride (39 mg, 0.067 mmol), to afford benzyl2-(cyanomethyl)-4-(2-(((S)-4-methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(17 mg, 0.026 mmol, 45%). ESI+ MS m/z 648.3 (100%) [M+H]⁺.

Step D:2-(4-(2-(((S)-4-Methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.Prepared according to the procedure of Example 375 Step F, substitutingbenzyl2-(cyanomethyl)-4-(2-(((S)-4-methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(17 mg, 0.026 mmol) to afford2-(4-(2-(((S)-4-methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(13.5 mg, 0.026 mmol, 100%). ESI+ MS m/z 514.3 (100%) [M+H]⁺.

Step E:2-(1-Acryloyl-4-(2-(((S)-4-methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.Prepared according to the procedure of Example 375 Step G, substituting2-(4-(2-(((S)-4-methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(13.5 mg, 0.026 mmol) to afford title compound2-(1-acryloyl-4-(2-(((S)-4-methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(EXAMPLE 444, 9.5 mg, 0.017 mmol, 65%). ESI+MS m/z 568.3 (100%) [M+H]⁺.

Example 445

2-(1-Acryloyl-4-(2-(((S)-4-methylmorpholin-3-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: tert-Butyl(3S)-3-(((4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)morpholine-4-carboxylate.Prepared according to the procedure of Example 375 Step C, substitutingbenzyl4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(65 mg, 0.118 mmol) and tert-butyl(R)-3-(hydroxymethyl)morpholine-4-carboxylate (76.6 mg, 0.353 mmol),purifying by flash chromatography eluting with 25-100% hex/EtOAc toafford tert-butyl(3S)-3-(((4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)morpholine-4-carboxylate(80 mg, 0.109 mmol, 92.8% yield). ESI+ MS m/z 734.3 (100%) [M+H]⁺.

Step B: Benzyl2-(cyanomethyl)-4-(2-(((S)-morpholin-3-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatehydrochloride. Prepared according to the procedure of Example 375 StepD, substituting tert-butyl(3S)-3-(((4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)morpholine-4-carboxylate(80 mg, 0.11 mmol) to afford benzyl2-(cyanomethyl)-4-(2-(((S)-morpholin-3-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatehydrochloride (73 mg, 0.11 mmol, 100%). ESI+ MS m/z 634.3 (100%) [M+H]⁺.

Step C: Benzyl2-(cyanomethyl)-4-(2-(((S)-4-methylmorpholin-3-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate.Prepared according to the procedure from Example 443 step C,substituting benzyl2-(cyanomethyl)-4-(2-(((S)-morpholin-3-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatehydrochloride (73 mg, 0.109 mmol), to afford benzyl2-(cyanomethyl)-4-(2-(((S)-4-methylmorpholin-3-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(27.6 mg, 0.042 mmol, 39%). ESI+ MS m/z 648.3 (100%) [M+H]⁺.

Step D:2-(4-(2-(((S)-4-Methylmorpholin-3-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.Prepared according to the procedure of Example 375 Step F, substitutingbenzyl2-(cyanomethyl)-4-(2-(((S)-4-methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(27.6 mg, 0.042 mmol) to afford2-(4-(2-(((S)-4-methylmorpholin-3-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(20.2 mg, 0.039 mmol, 100%). ESI+ MS m/z 514.3 (100%) [M+H]⁺.

Step E:2-(1-Acryloyl-4-(2-(((S)-4-methylmorpholin-3-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.Prepared according to the procedure of Example 375 Step G, substituting2-(4-(2-(((S)-4-methylmorpholin-3-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(20.2 mg, 0.0393 mmol) to afford title compound2-(1-acryloyl-4-(2-(((S)-4-methylmorpholin-3-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(EXAMPLE 445, 15 mg, 0.026 mmol, 67%). ESI+MS m/z 568.3 (100%) [M+H]⁺.

Example 446

2-(1-Acryloyl-4-(2-(((R)-4-methylmorpholin-3-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: tert-Butyl(3R)-3-(((4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)morpholine-4-carboxylate.Prepared according to the procedure of Example 375 Step C, substitutingbenzyl4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(65 mg, 0.118 mmol) and tert-butyl(S)-3-(hydroxymethyl)morpholine-4-carboxylate (76.6 mg, 0.353 mmol),purifying by flash chromatography eluting with 25-100% hex/EtOAc toafford tert-butyl(3R)-3-(((4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)morpholine-4-carboxylate(50 mg, 0.068 mmol, 58.0% yield). ESI+ MS m/z 734.3 (100%) [M+H]⁺.

Step B: Benzyl2-(cyanomethyl)-4-(2-(((R)-morpholin-3-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatehydrochloride. Prepared according to the procedure of Example 375 StepD, substituting tert-butyl(3R)-3-(((4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)morpholine-4-carboxylate(50 mg, 0.068 mmol) to afford benzyl2-(cyanomethyl)-4-(2-(((R)-morpholin-3-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatehydrochloride (46 mg, 0.068 mmol, 100%). ESI+ MS m/z 634.3 (100%)[M+H]⁺.

Step C: Benzyl2-(cyanomethyl)-4-(2-(((R)-4-methylmorpholin-3-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate.Prepared according to the procedure from Example 443 step C,substituting benzyl2-(cyanomethyl)-4-(2-(((R)-morpholin-3-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatehydrochloride (73 mg, 0.109 mmol), to afford benzyl2-(cyanomethyl)-4-(2-(((R)-4-methylmorpholin-3-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(23.0 mg, 0.036 mmol, 52%). ESI+ MS m/z 648.3 (100%) [M+H]⁺.

Step D:2-(4-(2-(((R)-4-Methylmorpholin-3-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.Prepared according to the procedure of Example 375 Step F, substitutingbenzyl2-(cyanomethyl-4-(2-(((R)-4-methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(23.0 mg, 0.036 mmol) to afford2-(4-(2-(((R)-4-methylmorpholin-3-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(18.2 mg, 0,036 mmol, 100%). ESI+ MS m/z 514.3 (100%) [M+H]⁺.

Step E:2-(1-Acryloyl-4-(2-(((R)-4-methylmorpholin-3-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.Prepared according to the procedure of Example 375 Step G, substituting2-(4-(2-(((R)-4-methylmorpholin-3-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(18.2 mg, 0.036 mmol) to afford title compound2-(1-acryloyl-4-(2-(((R)-4-methylmorpholin-3-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(EXAMPLE 446, 14 mg, 0.025 mmol, 69%). ESI+MS m/z 568.3 (100%) [M+H]⁺.

Example 447

2-((S)-1-Acryloyl-4-(2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: Benzyl(S)-4-(2-(((S)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)2-(cyanomethyl piperazine-1-carboxylate. Prepared according to theprocedure of Example 375 Step C, substituting benzyl(S)-4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(50 mg, 0.090 mmol) and tert-butyl(S)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (64.3 mg,0.271 mmol), purifying by flash chromatography eluting with 25-100%hex/EtOAc to afford benzyl(S)-4-(2-(((S)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(15 mg, 0.020 mmol, 220% yield). ESI+ MS m/z 754.3 (100%) [M+H]⁺.

Step B: Benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-4,4-difluoropyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatehydrochloride. Prepared according to the procedure of Example 375 StepD, substituting benzyl(S)-4-(2-(((S)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(18 mg, 0.024 mmol) to afford benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-4,4-difluoropyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatehydrochloride (16 mg, 0.023 mmol, 100%). ESI+ MS m/z 654.3 (100%)[M+H]⁺.

Step C: Benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate.Prepared according to the procedure from Example 443 step C,substituting benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-4,4-difluoropyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(16 mg, 0.023 mmol), to afford benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(16.0 mg, 0.024 mmol, 52%). ESI+ MS m/z 668.3 (100%) [M+H]⁺.

Step D:2-((S)-4-(2-(((S)-4,4-Difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.Prepared according to the procedure of Example 375 Step F, substitutingbenzyl(S)-2-(cyanomethyl)-4-(2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(16.0 mg, 0.024 mmol) to afford2-((S)-4-(2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(8.0 mg, 0.015 mmol, 63%). ESI+ MS m/z 534.3 (100%) [M+H]⁺.

Step E:2-((S)-1-Acryloyl-4-(2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.Prepared according to the procedure of Example 375 Step G, substituting2-((S)-4-(2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(8.0 mg, 0.015 mmol) to afford title compound2-((S)-1-acryloyl-4-(2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(EXAMPLE 447, 4 mg, 0.007 mmol, 45%) ESI+ MS m/z 588.3 (100%) [M+H]⁺.

Example 448

2-((S)-1-Acryloyl-4-(2-(((R)-4-methyl-7-oxa-4-azaspiro[2.5]octan-6-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: tert-Butyl(R)-6-(((4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)-7-oxa-4-azaspiro[2.5]octane-4-carboxylate.Prepared according to the procedure of Example 375 Step C, substitutingbenzyl(S)-4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(25 mg, 0.045 mmol) and tert-butyl(R)-6-(hydroxymethyl)-7-oxa-4-azaspiro[2.5]octane-4-carboxylate (33.0mg, 0.136 mmol), purifying by flash chromatography eluting with 25-100%hex/EtOAc to afford tert-butyl(R)-6-(((4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)-7-oxa-4-azaspiro[2.5]octane-4-carboxylate(35 mg, 0.0461 mmol, 100% yield). ESI+ MS m/z 760.3 (100%) [M+H]⁺.

Step B: Benzyl(S)-4-(2-(((R)-7-oxa-4-azaspiro[2.5]octan-6-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylatehydrochloride. Prepared according to the procedure of Example 375 StepD, substituting tert-butyl(R)-6-(((4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)-7-oxa-4-azaspiro[2.5]octane-4-carboxylate(35 mg, 0.046 mmol) to afford benzyl(S)-4-(2-(((R)-7-oxa-4-azaspiro[2.5]octan-6-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylatehydrochloride (32 mg, 0.046 mmol, 100%). ESI+MS m/z 660.3 (100%) [M+H]⁺.

Step C: Benzyl(S)-2-(cyanomethyl)-4-(2-(((R)-4-methyl-7-oxa-4-azaspiro[2.5]octan-6-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate.Prepared according to the procedure from Example 443 step C,substituting benzyl(S)-4-(2-(((R)-7-oxa-4-azaspiro[2.5]octan-6-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylatehydrochloride (32 mg, 0.046 mmol), to afford benzyl(S)-2-(cyanomethyl)-4-(2-(((R)-4-methyl-7-oxa-4-azaspiro[2.5]octan-6-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(31 mg, 0.046 mmol, 100%). ESI+ MS m/z 674.3 (100%) [M+H]⁺.

Step D:2-((S)-4-(2-(((R)-4-Methyl-7-oxa-4-azaspiro[2.5]octan-6-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.Prepared according to the procedure of Example 375 Step F, substitutingbenzyl(S)-2-(cyanomethyl)-4-(2-(((R)-4-methyl-7-oxa-4-azaspiro[2.5]octan-6-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(31.0 mg, 0.046 mmol) to afford2-((S)-4-(2-(((R)-4-methyl-7-oxa-4-azaspiro[2.5]octan-6-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(18.0 mg, 0.033 mmol, 72%). ESI+ MS m/z 540.3 (100%) [M+H]⁺.

Step E:2-((S)-1-Acryloyl-4-(2-(((R)-4-methyl-7-oxa-4-azaspiro[2.5]octan-6-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.Prepared according to the procedure of Example 375 Step G, substituting2-((S)-4-(2-(((R)-4-methyl-7-oxa-4-azaspiro[2.5]octan-6-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(18.0 mg, 0.033 mmol) to afford title compound2-((S)-1-acryloyl-4-(2-(((R)-4-methyl-7-oxa-4-azaspiro[2.5]octan-6-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(EXAMPLE 448, 5.8 mg, 0.010 mmol, 29%). ESI+ MS m/z 594.3 (100%) [M+H]⁺.

Example 449

2-(1-Acryloyl-4-(7-(2-(difluoromethyl)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A. Benzyl2-(cyanomethyl)-4-(7-(2-(difluoromethyl)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate.A mixture of benzyl2-(cyanomethyl)-4-(2-((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(30 mg, 0.0593 mmol), 1-Bromo-2-difluoromethylbenzene (36.8 mg, 0.178mmol), BINAP Palladacycle Gen. 3 (5.9 mg, 0.006 mmol), Cs₂CO₃ (77.3 mg,0.237 mmol) in dioxane (593 μl, 0.0593 mmol) was sparged with Ar for 5 mthen sealed and heated at 100° C. for 1 d. The reaction mixture wasloaded onto a silica gel samplet and purified by flash chromatographyeluting with a 1-10% MeOH/DCM (1% NH4OH) gradient to afford benzyl2-(cyanomethyl)-4-(7-(2-(difluoromethyl)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(12 mg, 0.019 mmol, 32%). ESI+ MS m/z 632.3 (100%) [M+H]+.

Step B:2-((S)-4-(2-(((R)-4-Methyl-7-oxa-4-azaspiro[2.5]octan-6-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.Prepared according to the procedure of Example 375 Step F, substitutingbenzyl2-(cyanomethyl)-4-(7-(2-(difluoromethyl)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(12.0 mg, 0.019 mmol) to afford2-(4-(7-(2-(difluoromethyl)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(9.5 mg, 0.019 mmol, 100%). ESI+ MS m/z 498.3 (100%) [M+H]+.

Step C:2-(1-Acryloyl-4-(7-(2-(difluoromethyl)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.Prepared according to the procedure of Example 375 Step G, substituting2-(4-(7-(2-(difluoromethyl)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(9.5 mg, 0.019 mmol) to afford title compound2-(1-acryloyl-4-(7-(2-(difluoromethyl)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(EXAMPLE 449, 4.2 mg, 0.008 mmol, 40%). ESI+ MS m/z 552.3 (100%) [M+H]+.

Example 450

2-((S)-1-Acryloyl-4-(2-(((R)-4-methylmorpholin-2-yl))methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: tert-Butyl(R)-2-(((4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)morpholine-4-carboxylate.Prepared according to the procedure of Example 443 Step A, substitutingbenzyl(S)-4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(95 mg, 0.172 mmol) and (R)—N-Boc-2-hydroxymethylmorpholine (112 mg,0.515 mmol), purifying by flash chromatography eluting with 25-100%hex/EtOAc to afford tert-butyl(R)-2-(((4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)morpholine-4-carboxylate(126 mg, 0.172 mmol, 100% yield). ESI+ MS m/z 734.3 (100%) [M+H]⁺.

Step B: Benzyl(S)-2-(cyanomethyl)-4-(2-(((R)-morpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatehydrochloride: Prepared according to the procedure of Example 375 StepD, substituting tert-butyl(R)-2-(((4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)morpholine-4-carboxylate(126 mg, 0.172 mmol) to afford benzyl(S)-2-(cyanomethyl)-4-(2-(((R)-morpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatehydrochloride (109 mg, 0.172 mmol, 100° %). ESI+ MS m/z 634.3 (100)%)[M+H]⁺.

Step C: Benzyl(S)-2-(cyanomethyl)-4-(2-(((R)-4-methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate.Prepared according to the procedure of Example 443 Step C, substitutingbenzyl(S)-2-(cyanomethyl)-4-(2-(((R)-4-methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(109 mg, 0.172 mmol) to afford benzyl(S)-2-(cyanomethyl)-4-(2-(((R)-4-methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(76 mg, 0.117 mmol, 68%). ESI+ MS m/z 648.3 (100%) [M+H]⁺.

Step D:2-((S)-4-(2-(((R)-4-Methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.Prepared according to the procedure of Example 375 Step F, substitutingbenzyl(S)-2-(cyanomethyl)-4-(2-(((R)-4-methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(76 mg, 0.117 mmol) to afford2-((S)-4-(2-(((R)-4-methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(57.1 mg, 0.111 mmol, 95%). ESI+ MS m/z 514.3 (100%) [M+H]⁺.

Step E:2-(1-Acryloyl-4-(2-(((R)-4-methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.Prepared according to the procedure of Example 375 Step G, substituting2-((S)-4-(2-(((R)-4-methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(56 mg, 0.11 mmol) to afford title compound2-((S)-1-acryloyl-4-(2-(((R)-4-methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(EXAMPLE 450, 50 mg, 0.088 mmol, 81%). ESI+MS m/z 568.3 (100%) [M+H]⁺.

Example 451

2-((S)-1-Acryloyl-4-(2-(((2R,5R)-4,5-dimethylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: tert-Butyl(2R,5R)-2-(((4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methy)-5-methylmorpholine-4-carboxylate.Prepared according to the procedure of Example 375 Step C, substitutingbenzyl(S)-4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(95 mg, 0.172 mmol) and tert-butyl(2R,5R)-2-(hydroxymethyl)-5-methylmorpholine-4-carboxylate (119 mg,0.515 mmol), purifying by flash chromatography eluting with 25-100%hex/EtOAc to afford tert-butyl(2R,5R)-2-(((4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methy)-5-methylmorpholine-4-carboxylate(128 mg, 0.171 mmol, 100% yield) ESI+ MS m/z 748.3 (100%) [M+H]⁺.

Step B: Benzyl(S)-2-(cyanomethyl)-4-(2-(((2R,5R)-5-methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate.Prepared according to the procedure of Example 375 Step D, substitutingtert-butyl(2R,5R)-2-(((4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)-5-methylmorpholine-4-carboxylate(128 mg, 0.171 mmol) to afford benzyl(S)-2-(cyanomethyl)-4-(2-(((2R,5R)-5-methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(111 mg, 0.171 mmol, 100%). ESI+ MS m/z 648.3 (100%) [M+H]⁺.

Step C: Benzyl(S)-2-(cyanomethyl-4-(2-((2R,5R)-4,5-dimethylmorpholin-2-yl)methoxy-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate.Prepared according to the procedure from Example 443 step C,substituting benzyl(S)-2-(cyanomethyl)-4-(2-(((2R,5R)-5-methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(111 mg, 0.171 mmol), to afford benzyl(S)-2-(cyanomethyl)-4-(2-(((2R,5R)-4,5-dimethylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(56 mg, 0.085 mmol, 49%). ESI+ MS m/z 662.3 (100%) [M+H]⁺.

Step D:2-((S)-4-(2-(((2R,5R)-4,5-Dimethylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.Prepared according to the procedure of Example 375 Step F, substitutingbenzyl(S)-2-(cyanomethyl)-4-(2-(((2R,5R)-4,5-dimethylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(56 mg, 0.085 mmol) to afford2-((S)-4-(2-(((2R,5R)-4,5-dimethylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(44.3 mg, 0.084 mmol, 99%). ESI+ MS m/z 528.3 (100%) [M+H]⁺.

Step E:2-((S)-1-Acryloyl-4-(2-(((2R,5R)-4,5-dimethylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.Prepared according to the procedure of Example 375 Step G, substituting2-((S)-4-(2-(((2R,5R)-4,5-dimethylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(43 mg, 0.081 mmol) to afford title compound2-((S)-1-acryloyl-4-(2-(((2R,5R)-4,5-dimethylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(EXAMPLE 451, 32 mg, 0.055 mmol, 68%). ESI+ MS m/z 582.3 (100%) [M+H]⁺.

Example 452

2-((S)-1-Acryloyl-4-(7-(naphthalen-1-yl)-2-(((R)-4,5,5-trimethylmorpholin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: tert-Butyl(R)-2-(((4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)-5,5-dimethylmorpholine-4-carboxylate.Prepared according to the procedure of Example 375 Step C, substitutingbenzyl(S)-4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(95 mg, 0.172 mmol) and tert-butyl(R)-2-(hydroxymethyl)-5,5-dimethylmorpholine-4-carboxylate (126 mg,0.515 mmol), purifying by flash chromatography eluting with 25-100%hex/EtOAc to afford tert-butyl(R)-2-(((4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)-5,5-dimethylmorpholine-4-carboxylate(131 mg, 0.172 mmol, 100% yield). ESI+ MS m/z 762.3 (100%) [M+H]⁺.

Step B: Benzyl(S)-2-(cyanomethyl)-4-(2-(((R)-5,5-dimethylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate.Prepared according to the procedure of Example 375 Step D, substitutingtert-butyl(R)-2-(((4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)-5,5-dimethylmorpholine-4-carboxylate(131 mg, 0.172 mmol) to afford benzyl(S)-2-(cyanomethyl)-4-(2-(((R)-5,5-dimethylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(114 mg, 0.172 mmol, 100%). ESI+ MS m/z 662.3 (100%) [M+H]⁺.

Step C: Benzyl(S)-2-(cyanomethyl)-4-(7-(naphthalen-1-yl)-2-(((R)-4,5,5-trimethylmorpholin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate.Prepared according to the procedure from Example 443 step C,substituting benzyl(S)-2-(cyanomethyl)-4-(2-(((R)-5,5-dimethylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(114 mg, 0.172 mmol), to afford benzyl(S)-2-(cyanomethyl)-4-(7-(naphthalen-1-yl)-2-(((R)-4,5,5-trimethylmorpholin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(77 mg, 0.114 mmol, 66%). ESI+ MS m/z 676.3 (100%) [M+H]⁺.

Step D:2-((S)-4-(7-(Naphthalen-1-yl)-2-(((R)-4,5,5-trimethylmorpholin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.Prepared according to the procedure of Example 375 Step F, substitutingbenzyl(S)-2-(cyanomethyl)-4-(7-(naphthalen-1-yl)-2-(((R)-4,5,5-trimethylmorpholin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(77 mg, 0.114 mmol) to afford2-((S)-4-(7-(naphthalen-1-yl)-2-(((R)-4,5,5-trimethylmorpholin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(47 mg, 0.087 mmol, 77%). ESI+ MS m/z 542.3 (100%) [M+H]⁺.

Step E:2-((S)-1-Acryloyl-4-(7-(naphthalen-1-yl)-2-(((R)-4,5,5-trimethylmorpholin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.Prepared according to the procedure of Example 1 Step G, substituting2-((S)-4-(7-(naphthalen-1-yl)-2-(((R)-4,5,5-trimethylmorpholin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(46 mg, 0.085 mmol) to afford title compound2-((S)-1-acryloyl-4-(7-(naphthalen-1-yl)-2-(((R)-4,5,5-trimethylmorpholin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(EXAMPLE 452, 36 mg, 0.060 mmol, 71%) ESI+ MS m/z 582.3 (100%) [M+H]⁺.

Example 453

1-[4-[7-(5,6-dimethyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step 1: 3-bromo-1,2,4-trimethyl-5-nitro-benzene. To a solution of1,2,4-trimethyl-5-nitro-benzene (10 g, 60 mmol, 1 eq) in DCE (200 mL)was added FeBr₃ (358 mg, 1.21 mmol, 0.02 eq), Fe (879 mg, 15.7 mmol,0.26 eq) following by Br₂ (11.6 g, 72.6 mmol, 3.74 mL, 1.2 eq) dropwise.After stirred at 25° C. for 1 hour, the reaction mixture was dilutedwith water (20 mL) and extracted with ethyl acetate (20 mL×3). Thecombined organic layers were washed with brine (20 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The crude product was slurried in water and collected byfiltration. 3-bromo-1,2,4-trimethyl-5-nitro-benzene (8.6 g, 34.9 mmol,58% yield, 99% purity) was obtained as a white solid.

Step 2: 3-bromo-2,4,5-trimethyl-aniline. To a solution of3-bromo-1,2,4-trimethyl-5-nitro-benzene (5.2 g, 21.3 mmol, 1 eq) in EtOH(100 mL) was added Fe (5.95 g, 107 mmol, 5 eq) and AcOH (12.8 g, 213mmol, 12.2 mL, 10 eq). The mixture was stirred at 60° C. for 3 hours.Upon completion, the reaction mixture was filtered and the filtrate wasconcentrated. The residue was purified by reversed phase flash [water(0.1% formic acid)/acetonitrile)]. The desired fractions were collectedand neutralized with saturated aqueous NaHCO₃, and then concentratedunder vacuum to remove MeCN and extracted with EtOAc (2×100 mL). Theorganic layers were dried over Na₂SO₄ and concentrated under vacuum togive 3-bromo-2,4,5-trimethyl-aniline (3.4 g, 14.3 mmol, 67% yield, 90%purity) as a yellow solid.

¹H NMR (400 MHz, chloroform-d) δ=6.51 (s, 1H), 3.56 (br s, 2H), 2.32 (s,3H), 2.31 (s, 3H), 2.26 (s, 3H).

Step 3: 4-bromo-5,6-dimethyl-1H-indazole.3-bromo-2,4,5-trimethyl-aniline (200 mg, 934.14 umol, 1 eq) wasdissolved in trifluoroborane; hydrofluoride (1.69 g, 7.71 mmol, 1.20 mL,8.25 eq, 40% in water) dropwise at 0° C. A cooled aqueous solution ofNaNO₂ (96.7 mg, 1.40 mmol, 1.5 eq) (in the minimum of water to saturatedaqueous). After addition, the mixture was stirred at 0° C. for 1 hourand 25° C. for 0.5 hour. NaNO₂ (64 mg, in the minimum of water tosaturated aqueous) was added at 0° C. and the mixture was stirred at 0°C. for 0.5 hour. Then, the resulting precipitate was filtered, washedwith (i-Pr)₂O (40 mL) and concentrated under vacuum which was directlyadded in one portion under N₂ to a stirred mixture of KOAc (183 mg, 1.87mmol, 2 eq) and 18-CROWN-6 (12.4 mg, 46.7 umol, 0.05 eq) in CHCl₃ (8mL). The mixture was stirred at 35° C. for 0.5 hour Upon completion, themixture was filtered and the filtrate was concentrated under vacuum. Theresidue was purified by silica gel chromatography (PE/EtOAc 100/1 to5/1) to give 4-bromo-5,6-dimethyl-1H-indazole (70 mg, 280 umol, 30%yield, 90% purity) as a yellow solid.

Step 4: 4-bromo-5,6-dimethyl-1-tetrahydropyran-2-yl-indazole. To asolution of 4-bromo-5,6-dimethyl-1H-indazole (290 mg, 1.29 mmol, 1 eq)in DCM (6 mL) was added TsOH·H₂O (24.5 mg, 129 umol, 0.1 eq), followedby DHP (217 mg, 2.58 mmol, 236 uL, 2 eq) and MeCN (1 mL). The mixturewas stirred at 25° C. for 5 hours. Upon completion, the mixture wasquenched with saturated aqueous NaHCO₃ solution (5 mL), diluted withwater (20 mL). layers were separated and the aqueous phase was extractedwith EtOAc (2×200 mL). Combined organic layers were dried over Na₂SO₄,filtered and concentrated under vacuum. The residue was purified bysilica gel chromatography (PE/EtOAc 100/1 to 25/1) to give4-bromo-5,6-dimethyl-1-tetrahydropyran-2-yl-indazole (320 mg, 828 umol,64% yield, 80% purity) as a yellow oil. LCMS [ESI, M+1]: 309.

¹H NMR (400 MHz, chloroform-d) δ=7.94 (s, 1H), 7.33 (s, 1H), 5.66 (dd,J=2.8, 9.2 Hz, 1H), 4.06-3.97 (m, 1H), 3.79-3.67 (m, 1H), 2.47 (s, 3H),2.44 (s, 3H), 2.16 (qd, J=4.4, 7.6 Hz, 1H), 2.06 (qd, J=3.2, 13.2 Hz,1H), 1.83-1.64 (m, 4H).

Step A: tert-butyl4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.tert-butyl4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(385 mg, 890 umol, 1 eq),4-bromo-5,6-dimethyl-1-tetrahydropyran-2-yl-indazole (303 mg, 979 umol,1.10 eq), Pd₂(dba)₃ (163 mg, 178 umol, 0.2 eq), RuPhos (166 mg, 356umol, 0.4 eq) and Cs₂CO₃ (725 mg, 2.23 mmol, 2.5 eq) in toluene (30 mL)was de-gassed and then heated to 90° C. for 8 hours under N₂. Uponcompletion, the mixture was filtered and the filtrate was concentratedunder vacuum. The residue was purified by silica gel chromatography(EtOAc/MeOH 100/1 to 5/1) to give tert-butyl4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 275 umol, 31% yield, 91% purity) as a yellow solid. LCMS [ESI,M+1]: 661.

Step B:7-(5,6-dimethyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine.To a solution of tert-butyl4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(190 mg, 288 umol, 1 eq) in DCM (0.4 mL) was added TFA (924 mg, 8.10mmol, 0.6 mL, 28.2 eq). The mixture was stirred at 25° C. for 1 hour.Upon completion, the mixture was concentrated under vacuum to give7-(5,6-dimethyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(220 mg, crude, 2TFA) as a yellow oil which was used directly into thenext step without further purification.

Step C:1-[4-[7-(5,6-dimethyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one.To a solution of7-(5,6-dimethyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(200 mg, 284 umol, 1 eq, 2 TFA) and TEA (574 mg, 5.68 mmol, 790 uL, 20eq) in DCM (4 mL) was added prop-2-enoyl prop-2-enoate (35.8 mg, 284umol, 1 eq) dropwise at −40° C. The mixture was stirred at −40° C. for30 minutes. Upon completion, the mixture was quenched with MeOH (0.5mL), diluted with water (5 mL) and then extracted with DCM (2×10 mL).The extracts were dried over Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by chromatography (Al₂O₃, EtOAc/MeOH100/1 to 10/1) and prep-HPLC (column: Gemini 150*25 5 u; mobile phase:[water (0.05% ammonia hydroxide v/v)-ACN]; B %: 35%-65%, 12 min). Thedesired fractions were collected and lyophilized to give title compound1-[4-[7-(5,6-dimethyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(EXAMPLE 453, 45.3 mg, 85.2 umol, two steps 30% yield, 99.7% purity) asa white solid. LCMS [ESI, M+1]: 531.

SFC condition: Column: Chiralcel OJ-3 100×4.6 mm I.D., 3 um, Mobilephase: methanol (0.05% DEA) in CO₂ from 5% to 40%, Flow rate: 3 mL/min,Wavelength: 220 nm.

¹H NMR (400 MHz, chloroform-d) δ=10.84 (br s, 1H), 8.02 (s, 1H), 7.13(s, 1H), 6.59 (dd, J=10.4, 16.8 Hz, 1H), 6.34 (dd, J=1.2, 16.8 Hz, 1H),5.79-5.68 (m, 1H), 4.40 (dd, J=4.8, 10.4 Hz, 1H), 4.26 (s, 2H), 4.17(dd, J=6.8, 10.4 Hz, 1H), 3.90-3.39 (m, 10H), 3.09 (br t, J=7.6 Hz, 1H),2.89-2.62 (m, 3H), 2.47 (s, 3H), 2.39 (s, 3H), 2.33 (s, 3H), 2.30-2.23(m, 1H), 2.09-1.97 (m, 1H), 1.91-1.69 (m, 3H).

Example 454

2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[2-(4,4-difluoro-1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step 1: 4,4-difluoropiperidine. To a solution of tert-butyl4,4-difluoropiperidine 1-carboxylate (2.0 g 9.04 mmol, 1.0 eq) in DCM(0.50 mL) was added TFA (770 mg, 6.75 mmol 0.50 mL, 7.47 e⁻¹ eq). Themixture was stirred at 25° C. for 0.5 hour. After completion, thereaction mixture was concentrated under vacuum to give the product4,4-difluoropiperidine (1.50 g, crude, TFA) as yellow oil which was usedfor the next step without further purification.

Step 2: 1-(2-benzyloxyethyl)-4,4-difluoro-piperidine. To a solution of4,4-difluoropiperidine (1.50 g, 6.38 mmol, 1.0 eq, TFA) in MeCN (20.0mL) was added NaOH (765 mg, 19.1 mmol, 3.0 eq). The mixture was stirredat 25° C. for 0.5 hour. Then 2-bromoethoxymethylbenzene (1.65 g, 7.65mmol, 1.21 mL, 1.20 eq) and KI (212 mg, 1.28 mmol, 0.20 eq) was added tothe above liquid, the mixture was stirred at 90° C. for 12 hours. Aftercompletion, the reaction mixture was added water (20.0 mL), and thenextracted with EA (3×20.0 mL). The combined organic layers were driedover by Na₂SO₄, filtered and concentrated. The residue was purified bycolumn chromatography (SiO₂, Petroleum ether:Ethyl acetate-10:1 to 0:1)to give 1-(2-benzyloxyethyl)-4,4-difluoro-piperidine (600 mg, 2.35 mmol,two steps 37% yield) as yellow oil.

¹H NMR (400 MHz, Chloroform-d) δ 7.41-7.29 (m, 5H), 4.54 (s, 2H),3.82-3.72 (m, 2H), 3.33-2.94 (m, 6H), 2.37-2.15 (m, 4H).

Step 3: 2-(4,4-difluoro-1-piperidyl)ethanol. A solution of1-(2-benzyloxyethyl)-4,4-difluoro-piperidine (400 mg, 1.57 mmol, 1.0 eq)and Pd/C (200 mg, 10% purity) in EtOH (5.0 mL) was stirred under H₂ (15Psi) atmosphere at 25° C. for 12 hours. After completion, the reactionmixture was filtered through Celite, the filter cake was washed with THF(10.0 mL). The filtrate was collected and concentrated to give theproduct 2-(4,4-difluoro-1-piperidyl)ethanol (170 mg, 1.03 mmol, 66%yield) as colorless oil. The product was used for the next step withoutfurther purification.

¹H NMR (400 MHz, Chloroform-d) δ 3.84-3.70 (m, 2H), 2.98-2.89 (m, 4H),2.86-2.80 (m, 3H), 2.24-2.11 (m, 4H).

Step A: tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-(2-(4,4-difluoro-1-piperidyl)ethoxyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.To a solution of 2-(4,4-difluoro-1-piperidyl)ethanol (102 mg, 619 umol,3.0 eq) in toluene (3.0 mL) and tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(120 mg, 206 umol, 1.0 eq) was added t-BuONa (39.7 mg, 413 umol, 2.0eq), the mixture was stirred at 0° C. for 0.5 hour. After completion,the reaction mixture was added water (10.0 mL) and extracted with EA(3×10.0 mL). The organic layer was dried over Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by reversed phaseflash (C18, 0.1% NH₃·H₂O, 0-60% MeCN) to give the product tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[2-(4,4-difluoro-1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(90.0 mg, 132 umol, 64% yield) as yellow oil. LCMS [ESI, M+1]: 682.

Step B:2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[2-(4,4-difluoro-1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[2-(4,4-difluoro-1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(30.0 mg, 44.0 umol, 1.0 eq) in DCM (0.5 mL) was added TFA (770 mg, 6.75mmol, 0.50 mL, 154 eq). The mixture was stirred at 25° C. for 0.5 hour.After completion, the mixture was concentrated. The residue was adjustedwith saturated NaHCO₃ aqueous to pH˜7, then extracted with EA (3×5.0mL). The organic layer was dried over Na₂SO₄, filtered and concentratedto give the product2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[2-(4,4-difluoro-1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(26.0 mg, crude) as yellow oil which was used for the next step withoutfurther purification. LCMS [ESI, M+1]: 582.

Step C:2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[2-(4,4-difluoro-1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[2-(4,4-difluoro-1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(26.0 mg, 44.7 umol, 1.0 eq) and DIEA (69.3 mg, 536 umol, 93.4 uL, 12.0eq) in DCM (1.0 mL) was added prop-2-enoyl prop-2-enoate (8.45 mg, 67.0umol, 1.50 eq). The mixture was stirred at 0° C. for 0.5 hour. Aftercompletion, the mixture was quenched by addition MeOH (1.0 mL), and thenconcentrated to give a residue. Then the residue was purified byprep-HPLC (column: Gemini 150*25 5 u; mobile phase: [water (0.05%ammonia hydroxide v/v)-ACN]; Bo: 47%-77%, 12 min) to give title compound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[2-(4,4-difluoro-1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 454, 6.35 mg, 9.82 umol, two steps 22% yield, 98% purity) aswhite solid. LCMS [ESI, M+1]: 636.

¹H NMR (400 MHz, Chloroform-d) δ 7.76 (br d, J=8.0 Hz, 1H), 7.63 (t,J=7.2 Hz, 1H), 7.53 (d, J=7.2 Hz, 1H), 7.49-7.40 (m, 1H), 7.34 (t, J=7.8Hz, 1H), 7.27-7.17 (m, 1H), 6.67-6.54 (m, 1H), 6.40 (br d, J=16.4 Hz,1H), 5.83 (br d, J=11.2 Hz, 1H), 5.20-4.56 (m, 1H), 4.50-4.35 (m, 3H),4.22-4.01 (m, 2H), 3.98-3.75 (m, 2H), 3.66-3.57 (m, 1H), 3.53-3.36 (m,1H), 3.31-2.98 (m, 4H), 2.91-2.80 (m, 3H), 2.79-2.49 (m, 6H), 2.09-1.94(m, 4H).

Example 455

2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[2-(3,3-difluoro-1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step 1: 1-(2-benzyloxyethyl)-3,3-difluoro-piperidine. To solution of3,3-difluoropiperidine (1.0 g, 6.35 mmol, 1.0 eq, HCl) in MeCN (6.0 mL)was added NaOH (761 mg, 19.0 mmol, 3.0 eq) in one portion at 25° C. Themixture was stirred at 25° C. for 5 minutes, then2-bromoethoxymethylbenzene (1.64 g, 7.61 mmol, 1.20 mL, 1.20 eq) and KI(211 mg, 1.27 mmol, 0.20 eq) was added. The mixture was stirred at 90°C. for 12 hours. After completion, the reaction mixture was added H₂O(15.0 mL), and then extracted with EA (3×20.0 mL). The combined organiclayers were dried over by Na₂SO₄, filtered and concentrated to give aresidue. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate 10:1 to 5:1) to give1-(2-benzyloxyethyl)-3,3-difluoro-piperidine (1.40 g, 5.48 mmol, 86%yield) as colorless oil.

¹H NMR (400 MHz, Chloroform-d) δ 7.38-7.31 (m, 5H), 4.56 (s, 2H), 3.64(t, J=5.8 Hz, 2H), 2.79-2.73 (m, 4H), 2.55 (t, J=5.4 Hz, 2H), 1.85-1.85(m, 2H), 1.82-1.76 (m, 2H).

Step 2: 2-(3,3-difluoro-1-piperidyl)ethanol. To solution of1-(2-benzyloxyethyl)-3,3-difluoro-piperidine (400 mg, 1.57 mmol, 1.0 eq)in MeCN (5.0 mL) was added Pd/C (200 mg, 10% purity) under N₂. Thesuspension was degassed under vacuum and purged with H₂ several times.The mixture was stirred under H₂ (15 psi) at 40° C. for 1 hours. Aftercompletion, the reaction mixture was filtered and concentrated to give2-(3,3-difluoro-1-piperidyl)ethanol (240 mg, 1.45 mmol, 93% yield) ascolorless oil. The product was used for the next step without furtherpurification.

¹H NMR (400 MHz, Chloroform-d) δ 3.64 (t, J=5.4 Hz, 2H), 2.73 (t, J=11.2Hz, 2H), 2.63 (t, J=5.4 Hz, 2H), 2.54 (t, J=5.2 Hz, 2H), 1.97-1.87 (m,2H), 1.82-1.76 (m, 2H).

Step A: tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[2-(3,3-difluoro-1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.A mixture of tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(230 mg, 396 umol, 1.0 eq), 2-(3,3-difluoro-1-piperidyl)ethanol (196 mg,1.19 mmol, 3.0 eq), t-BuONa (114 mg, 1.19 mmol, 3.0 eq) in toluene (5.0mL) was degassed and purged with N₂ for 3 times, and then the mixturewas stirred at 0° C. for 0.5 hour under N₂ atmosphere. After completion,the reaction mixture was quenched by H₂O (5.0 mL) and extracted with EA(3×10.0 mL). The combined organic layer was washed with saturated NaClaqueous solution (20.0 mL), dried over Na₂SO₄, filtered and concentratedto give a residue. The residue was purified by column chromatography(SiO₂, Petroleum ether/Ethyl acetate=3:1 to 0:1) to give tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[2-(3,3-difluoro-1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(250 mg, 344 umol, 87% yield, 94% purity) as yellow oil.

¹H NMR (400 MHz, Chloroform-d) δ 7.77 (d, J=8.0 Hz, 1H), 7.63 (t, J=8.0Hz, 1H), 7.54 (d, J=7.2 Hz, 1H), 7.50-7.42 (m, 1H), 7.37-7.33 (m, 1H),7.27-7.20 (m, 1H), 4.67-4.64 (m, 1H), 4.48-4.39 (m, 3H), 4.06 (d, J=12.8Hz, 1H), 4.01-3.80 (m, 3H), 3.60 (d, J=4.0 Hz, 1H), 3.37 (dd, J=3.6,13.6 Hz, 1H), 3.27-3.10 (m, 3H), 2.97-2.90 (m, 3H), 2.84-2.78 (m, 3H),2.61-2.57 (m, 2H), 1.89-1.85 (m, 3H), 1.72-1.54 (m, 3H), 1.53 (s, 9H).

Step B:2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[2-(3,3-difluoro-1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a mixture of tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[2-(3,3-difluoro-1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(200 mg, 293 umol, 1.0 eq) in DCM (1.50 mL) was added TFA (2.31 g, 20.3mmol, 1.50 mL, 69.0 eq) in one portion at 25° C. under N₂. The mixturewas stirred at 25° C. for 0.5 hour. After completion, the mixture wasconcentrated to give2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[2-(3,3-difluoro-1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(400 mg, crude, 2TFA) as yellow solid. The product was used for the nextstep without further purification. LCMS [ESI, M+1]: 582.

Step C:2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[2-(3,3-difluoro-1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a mixture of2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[2-(3,3-difluoro-1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(400 mg, 494 umol, crude, 2TFA) and TEA (727 mg, 7.18 mmol, 1.0 mL) inDCM (2.0 mL) was added prop-2-enoyl prop-2-enoate (100 mg, 793 umol) inone portion at 0° C. under N₂. The mixture was stirred at 0° C. for 0.5hour. After completion, the mixture was quenched by addition MeOH (3.0mL) at 0° C., and then concentrated to give a residue. Then the residuewas purified by prep-HPLC (column: Phenomenex Gemini 150*25 mm*10 um;mobile phase: [water (10.0 mM NH₄HCO₃)-ACN]; B %: 57%-87%, 10 min.) andlyophilized to give title compound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[2-(3,3-difluoro-1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 455, 48.4 mg, 75.8 umol, 26% yield, 99% purity) as white solid.

SFC condition: 100% e.e.

¹H NMR (400 MHz, Chloroform-d) δ 7.78 (d, J=8.0 Hz, 1H), 7.64 (t, J=7.4Hz, 1H), 7.54 (d, J=7.6 Hz, 1H), 7.50-7.43 (m, 1H), 7.36 (t, J=7.8 Hz,1H), 7.27-7.21 (m, 1H), 6.60-6.58 (m, 1H), 6.44-6.39 (m, 1H), 5.85 (d,J=10.4 Hz, 1H), 5.10-4.66 (m, 1H), 4.49-4.40 (m, 3H), 4.18-4.08 (m, 2H),3.94-3.89 (m, 1H), 3.85-3.73 (m, 1H), 3.63-3.60 (m, 1H), 3.50-3.41 (m,1H), 3.33-3.02 (m, 4H), 2.94-2.76 (m, 6H), 2.64-2.61 (m, 3H), 1.95-1.85(m, 2H), 1.80-1.78 (m, 2H). LCMS [ESI, M+1]: 636.

Example 456

5,6-dimethyl-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-(4-prop-2-enoylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-1,3-dihydrobenzimidazol-2-one

Insert Step 1: 2-bromo-3,4-dimethyl-6-nitro-aniline. To a solution of4,5-dimethyl-2-nitro-aniline (5 g, 30.1 mmol, 1 eq) in CHCl₃ (100 mL)was added Br₂ (7.21 g, 45.1 mmol, 2.33 mL, 1.5 eq) dropwise at 10° C.The reaction, mixture was stirred at 10° C. for 30 mins and 25° C. for30 mins. After completion, the reaction mixture was washed withsaturated with NaHCO₃ aqueous (80 mL). The aqueous was extracted withCHCl₃ (30 mL). The combined organic phase was dried over Na₂SO₄,filtered through a pad of silica gel, and then concentrated to dryness.2-bromo-3,4-dimethyl-6-nitro-aniline (7 g, 28.5 mmol, 95% yield, 99.7%purity) was obtained as yellow solid. LCMS [ESI, M+3]: 247

Step 2: 3-bromo-1,2-dimethyl-4,5-dinitro-benzene. To a solution of2-bromo-3,4-dimethyl-6-nitro-aniline (7 g, 28.6 mmol, 1 eq) in TFA (50mL) was added hydrogen peroxide (25.9 g, 229 mmol, 22.0 mL, 30% purity,8.0 eq) dropwise at 10° C. The reaction mixture was stirred at 10° C.for 30 mins and 25° C. for 30 mins, and then at 40° C. for another 2hrs. The reaction mixture was cooled to 5-10° C. and then was filtered.The filter cake was washed with PE (3×20 mL). The solid was then driedunder reduced pressure at 50° C.3-bromo-1,2-dimethyl-4,5-dinitro-benzene (5 g, 18.2 mmol, 64% yield) wasobtained as yellow solid.

Step A: tert-butyl4-[7-(2,3-dimethyl-5,6-dinitro-phenyl)-2-[((2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a mixture of tert-butyl 4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(250 mg, 578 umol, 1 eq), 3-bromo-1,2-dimethyl-4,5-dinitro-benzene (318mg, 1.16 mmol, 2 eq), Pd₂(dba)₃ (52.9 mg, 57.8 umol, 0.1 eq), RuPhos(40.5 mg, 86.7 umol, 0.15 eq) and Cs₂CO₃ (377 mg, 1.16 mmol, 2 eq) intoluene (25 mL) was degassed and purged with N₂ for 3 times, and thenthe mixture was stirred at 90° C. for 8 hours under N₂ atmosphere. Thereaction mixture was diluted with H₂O (100 mL×1) and ethyl acetate (100mL×2). The separated organic phase was washed with brine (100 mL×1),dried over sodium sulfate, filtered and concentrated under reducedpressure to give a residue. The residue was purified by silica gelchromatography (SiO₂, Ethyl acetate/MeOH=50/1 to 3/1) and reversed phaseflash [water (0.1% FA)/acetonitrile]. The desired fractions werecollected and neutralized with saturated NaHCO₃ solution and extractedwith ethyl acetate (1×100 mL). The separated organic layer was driedover sodium sulfate, filtered and concentrated under vacuum. tert-butyl4-[7-(2,3-dimethyl-5,6-dinitro-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(22.0 mg, 140 umol, 6% yield, 99.7% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 627.

Step B: tert-butyl4-[7-(2,3-diamino-5,6-dimethyl-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of tert-butyl4-[7-(2,3-dimethyl-5,6-dinitro-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(120 mg, 191 umol, 1 eq) in MeOH (10 mL) was added Pd/C (24.0 mg, 10%purity) under N₂. The suspension was degassed under vacuum and purgedwith H₂ for several times. The mixture was stirred under H₂ (15 psi) at25° C. for 1 hour. The catalyst was filtered off and the filtrate wasconcentrated under vacuum. tert-butyl4-[7-(2,3-diamino-5,6-dimethyl-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(100 mg, crude) was obtained as a yellow solid and used into next stepwithout further purification. LCMS [ESI, M+1]: 567.

Step C: tert-butyl4-[7-(5,6-dimethyl-2-oxo-1,3-dihydrobenzimidazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of tert-butyl4-[7-(2,3-diamino-5,6-dimethyl-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(100 mg, 176 umol, 1 eq) in THF (10 mL) was added CDI (57.2 mg, 353umol, 2 eq). After stirred at 50° C. for 1 h, CDI (171 mg) was added andthe mixture was stirred at 70° C. for further 3 hours. The reactionmixture was quenched with H₂O (3 mL×1), and then extracted with ethylacetate (2×20 mL). The combined organic layers were washed with brine(1×10 mL), dried over sodium sulfate, filtered and concentrated undervacuum. The residue was purified by prep-HPLC (column: Luna C18 150*25 5u; mobile phase: [water (0.225% FA)-ACN]; B %: 17%-47%, 10 min). Thedesired fractions were collected and neutralized with saturated NaHCO₃solution and extracted with ethyl acetate (1×30 mL). The separatedorganic layer was dried over sodium sulfate, filtered and concentratedunder vacuum. tert-butyl4-[7-(5,6-dimethyl-2-oxo-1,3-dihydrobenzimidazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(20.0 mg, 33.7 umol, two steps 19% yield, 100% purity) was obtained as ayellow solid. LCMS [ESI, M+1]: 593.

Step D:5,6-dimethyl-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-1,3-dihydrobenzimidazol-2-one.Toa solution of tert-butyl4-[7-(5,6-dimethyl-2-oxo-1,3-dihydrobenzimidazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(16.0 mg, 27.0 umol, 1 eq) in dioxane (2 mL) was added HCl/dioxane (4 M,101 uL, 15 eq) at 0° C. After stirred at 25° C. for 0.5 h, the mixturewas concentrated under vacuum.5,6-dimethyl-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-1,3-dihydrobenzimidazol-2-one(20.0 mg, crude, HCl) was obtained as a yellow oil and used into nextstep without further purification. LCMS [ESI, M+1]: 493.

Step E:5,6-dimethyl-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-(4-prop-2-enoylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-1,3-dihydrobenzimidazol-2-one.To a mixture of5,6-dimethyl-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-1,3-dihydrobenzimidazol-2-one(20.0 mg, 37.8 umol, 1 eq, HCl) and TEA (38.3 mg, 378 umol, 52.6 uL, 10eq) in DCM (2 mL) was added prop-2-enoyl prop-2-enoate (4.77 mg, 37.8umol, 1 eq) in portion at −40° C. After stirred at −40° C. for 30 mins,the reaction mixture was quenched with saturated NaHCO₃ solution (0.5mL) at 0° C., and then extracted with CH₂Cl₂ (2×10 mL). The combinedorganic layers were washed with brine (1×10 mL), dried over sodiumsulfate, filtered and concentrated under vacuum to give a residue. Theresidue was purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B %: 10%-37%, 9min). The desired fractions were collected and concentrated underreduced pressure to remove ACN, and then lyophlizated. Title compound5,6-dimethyl-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-(4-prop-2-enoylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-1,3-dihydrobenzimidazol-2-one(EXAMPLE 456, 3.15 mg, 5.25 umol, two steps 14% yield, 98.8% purity,HCOOH) was obtained as a brown solid. LCMS [ESI, M+1]: 547.

¹H NMR (400 MHz, methanol-d₄) 6.90-6.81 (m, 1H), 6.80-6.72 (m, 1H), 6.28(br d, J=16.8 Hz, 1H), 5.82 (br d, J=10.4 Hz, 1H), 4.72-4.46 (m, 2H),4.32-4.01 (m, 2H), 3.93-3.53 (m, 101H), 3.53-3.38 (m, 1H), 3.21-3.02 (m,2H), 2.98 (s, 3H), 2.95-2.58 (m, 2H), 2.48-2.32 (m, 1H), 2.31 (br s,3H), 2.29 (br s, 3H), 2.19-1.94 (m, 3H).

Example 457

1-[4-[7-(5,6-dimethyl-1H-indol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step 1:(E)-2-(2-bromo-3,4-dimethyl-6-nitro-phenyl)-N,N-dimethyl-ethenamine. Toa solution of 3-bromo-1,2,4-trimethyl-5-nitro-benzene (2 g, 8.19 mmol, 1eq) in DMF (20 mL) was added DMFDMA (5.86 g, 49.2 mmol, 6.53 mL, 6 eq).The mixture was stirred at 130° C. for 10 hours. Upon completion, themixture was concentrated under vacuum to give(E)-2-(2-bromo-3,4-dimethyl-6-nitro-phenyl)-N,N-dimethyl-ethenamine (2.5g, crude) as a brown oil which was used directly into the next stepwithout further purification.

Step 2: 4-bromo-5,6-dimethyl-1H-indole. To a solution of(E)-2-(2-bromo-3,4-dimethyl-6-nitro-phenyl)-N,N-dimethyl-ethenamine (2.5g, 8.36 mmol, 1 eq) in EtOH (50 mL) was added Fe (2.33 g, 41.8 mmol, 5eq) and AcOH (5.02 g, 83.6 mmol, 4.78 mL, 10 eq). The mixture wasstirred at 60° C. for 2 hours. Upon completion, the mixture was filteredand the filtrate was concentrated. The mixture was adjusted pH=7 withsaturated NaHCO₃ aqueous solution and extracted with ethyl acetate (50mL×2). The combined organic layers were washed with brine (50 mL), driedover Na₂SO₄ and concentrated under vacuum. The residue was purified bysilica gel chromatography (PE/EtOAc 1/0 to 50/1) to give4-bromo-5,6-dimethyl-1H-indole (380 mg, 1.46 mmol, two steps yield 18%,86% purity) as a yellow oil.

¹H NMR (400 MHz, chloroform-d) δ=8.12 (br s, 1H), 7.20-7.10 (m, 2H),6.59-6.52 (m, 1H), 2.47 (s, 3H), 2.43 (s, 3H).

Step 3:2-[(4-bromo-5,6-dimethyl-indol-1-yl)methoxy]ethyl-trimethyl-silane. To asolution of 4-bromo-5,6-dimethyl-1H-indole (450 mg, 2.01 mmol, 1 eq) inTHF (9 mL) was added NaH (161 mg, 4.02 mmol, 60% purity, 2 eq) at 0° C.The reaction was stirred at 0° C. for 15 minutes under N₇. The reactionwas allowed to warm to 25° C. and stirred for 0.5 hour. The reaction waschilled again to 0° C. And SEM-Cl (502 mg, 3.01 mmol, 533 uL, 1.5 eq) inTHF (100 uL) was added drop-wise at 0° C. After stirring for 5 minutes,the mixture was allowed to warm to room temperature (25° C.) and stirredfor another 5 hours. Upon completion, the mixture was quenched withsaturated aqueous ammonium chloride solution (20 mL), diluted with water(10 mL), and then extracted with ethyl acetate (2×30 mL). The extractswere dried over Na₂SO₄, filtered and concentrated under vacuum. Theresidue was purified by silica gel chromatography (PE/EtOAc 1/0 to 50/1)to give2-[(4-bromo-5,6-dimethyl-indol-1-yl)methoxy]ethyl-trimethyl-silane (440mg, 1.18 mmol, 59% yield, 95% purity) as a yellow oil.

¹H NMR (400 MHz, chloroform-d) δ=7.25 (s, 1H), 7.11 (d, J=3.2 Hz, 1H),6.51 (d, J=2.8 Hz, 1H), 5.43 (s, 2H), 3.52-3.40 (m, 2H), 2.47 (s, 3H),2.46 (s, 3H), 0.92-0.87 (m, 2H), −0.01-−0.08 (m, 9H).

Step A: tert-butyl 4-[7-[5,6-dimethyl-1-(2-trimethylsilylethoxymethyl)indol-4-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.tert-butyl4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(Intermediate 66, 450 mg, 1.04 mmol, 1 eq),2-[(4-bromo-5,6-dimethyl-indol-1-yl)methoxy]ethyl-trimethyl-silane (406mg, 1.14 mmol, 1.1 eq), Pd₂(dba)₃ (191 mg, 208 umol, 0.2 eq), RuPhos(194 mg, 416 umol, 0.4 eq) and Cs₂CO₃ (847 mg, 2.60 mmol, 2.5 eq) intoluene (30 mL) was de-gassed and then heated to 90° C. for 8 hoursunder N₂. Upon completion, the mixture was filtered and the filtrate wasconcentrated under vacuum. The residue was purified by silica gelchromatography (EtOAc/MeOH 50/1 to 10/1) to give tert-butyl4-[7-[5,6-dimethyl-1-(2-trimethylsilylethoxymethyl)indol-4-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(106 mg, 135 umol, 13% yield, 90% purity) as a yellow solid. LCMS [ESI,M+1]: 706.

Step B: tert-butyl4-[7-(5,6-dimethyl-1H-indol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of tert-butyl4-[7-[5,6-dimethyl-1-(2-trimethylsilylethoxymethyl)indol-4-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(70 mg, 99.2 umol, 1 eq) in DMF (0.35 mL) was added TBAF (I M in THF,496 uL, 5 eq) followed by ethane-1,2-diamine (8.94 mg, 149 umol, 9.95uL, 1.5 eq). The mixture was stirred at 85° C. for 3 hours. Uponcompletion, the mixture was diluted with EtOAc (3 mL) and water (2 mL).The separated organic layer was dried over Na₂SO₄ and concentrated undervacuum. The residue was purified by prep-TLC (DCM/MeOH 10/1) to givetert-butyl4-[7-(5,6-dimethyl-1H-indol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(50 mg, 60.8 umol, 61% yield, 70% purity) as a yellow oil. LCMS [ESI,M+1]: 576.

Step C:7-(5,6-dimethyl-1H-indol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine.To a solution of tert-butyl4-[7-(5,6-dimethyl-1/1-indol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(45 mg, 78.2 umol, 1 eq) in DCM (70 uL) was added TFA (89.1 mg, 782umol, 57.9 uL, 10 eq). The mixture was stirred at 25° C. for 0.5 hour.Upon completion, the mixture was concentrated under vacuum to give7-(5,6-dimethyl-1H-indol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(60 mg, crude, 2 TFA) as a yellow oil which was used directly into thenext step without further purification.

Step D:1-[4-[7-(5,6-dimethyl-1H-indol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one.To a solution of 7-(5,6-dimethyl-1H-indol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(55 mg, 78.2 umol, 1 eq, 2 TFA) and TEA (158 mg, 1.56 mmol, 218 uL, 20eq) in DCM (1 mL) was added prop-2-enoyl prop-2-enoate (9.86 mg, 78.2umol, 1 eq) dropwise at −40° C. The mixture was stirred at −40° C. for30 minutes. Upon completion, the mixture was quenched with MeOH (0.5mL), diluted with water (5 mL) and then extracted with DCM (2×10 mL).The organic layers were dried over Na₂SO₄, filtered and concentratedunder vacuum. The residue was purified by chromatography (Al₂O₃,EtOAc/MeOH 100/1 to 10/1) and prep-HPLC (column: Phenomenex Synergi C18150*25*10 um; mobile phase: [water (0.1% TFA)-ACN]; B %: 16%-43%, 12min). The desired fractions were collected and neutralized withsaturated aqueous NaHCO₃, extracted with DCM (2×15 mL). The organiclayers were dried over Na₂SO₄ and concentrated under vacuum to givetitle compound1-[4-[7-(5,6-dimethyl-1H-indol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(EXAMPLE 457, 9.81 mg, 18.3 umol, two steps 23% yield, 98.8% purity) asa brown solid. LCMS [ESI, M+1]: 530.

SFC condition: OJ-3S_3_5_40_3 ML Column. Chiralcel OJ-3 100×4.6 mm I.D.,3 um Mobile phase: methanol (0.05% DEA) in CO₂ from 5% to 40% Flow rate:3 mL/min Wavelength: 220 nm.

¹H NMR (400 MHz, chloroform-d) δ=8.22 (br s, 1H), 7.09 (s, 1H),7.07-7.03 (m, 1H), 6.60 (dd, J=10.8, 16.8 Hz, 1H), 6.53-6.48 (m, 1H),6.34 (dd, J=2.0, 16.9 Hz, 1H), 5.76 (dd, J=2.0, 10.4 Hz, 1H), 4.49-4.10(m, 4H), 3.81 (br s, 2H), 3.76-3.38 (m, 8H), 3.13 (br t, J=7.2 Hz, 1H),3.02-2.56 (m, 3H), 2.50 (s, 3H), 2.39 (s, 3H), 2.36 (s, 3H), 2.34-2.25(m, 1H), 2.13-2.06 (m, 1H), 1.84-1.71 (m, 3H).

Example 458

2-((S)-1-(but-2-ynoyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: 1-bromo-8-methylnaphthalene: To a solution of1,8-dibromonaphthalene (33.8 g, 118 mmol) in THF (200 mL) cooled to −78°C. was added butyllithium (49.6 ml, 124 mmol) at such a rate that theinternal temperature did not exceed −69° C. After complete addition, thereaction was cooled to −78° C., and methyl iodide (14.8 ml, 236 mmol)was added in a bolus such that the internal temp increased to −40° C.After methyl iodide addition, the dry ice/acetone bath was removed andthe reaction warmed to room temperature. The reaction was next pouredinto brine and the aqueous layer extracted with EtOAc (300 mL) and theorganics separated. The organics were next dried over MgSO4 andconcentrated in vacuo and the residue chromatographed using hexanes aseluent to give a white solid (24 g). The solid was next slurried in IPA(ca. 60 mL) and the slurry heated to 60° C. at which point the solidsdissolved. The solution was removed from heating and cooled to roomtemperature over 2 hrs. The resulting slurry was filtered and the solidsdried in vacuo to give 1-bromo-8-methylnaphthalene (16 g, 72.4 mmol, 61%yield)>95% purity.

Step B: benzyl(S)-2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:A solution of xantphos (4.5 g, 7.8 mmol) and Pd₂(dba)₃ (3.5 g, 3.9 mmol)in dioxane (100 mL) was degassed with Argon for 15 minutes, followed byheating the solution for 20 minutes at 100° C. The solution was cooledto room temperature and benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(9.8 g, 19 mmol), 1-bromo-8-methylnaphthalene (13 g, 58 mmol) and Cs₂CO₃(32 g, 97 mmol), Pd₂(dba)₃ (3.5 g, 3.9 mmol) were added to the solutionand the mixture was degassed for an additional 20 minutes with Argon andthe reaction heated to 100° C. overnight. The reaction was next cooledto room temperature and filtered through GFF paper and the filtrate wasconcentrated in vacuo. The residue was next chromatographed 3 timesusing 1->10% (MeOH+2% NH4OH)/DCM to give benzyl(S)-2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(7.8 g, 12 mmol, 62% yield) ESI+APCI MS m/z 646.3 [M+H]⁺.

Step C:2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:A solution of benzyl(S)-2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(7.8 g, 12 mmol) in 1:1 EtOH/THF (100 mL) was degassed with N₂ for 5minutes followed by addition of Pd/C (2.6 g, 2.4 mmol). The slurry wasnext degassed under vacuum and backfilled with H₂ (3×). On the thirdback fill the mixture was stirred under a balloon of hydrogen forovernight. The slurry was again degassed with N₂ and the slurry filteredthrough celite. The combined filtrate was concentrated in vacuo and thesolids chromatographed using 1->10% (MeOH+2% NH4OH)/DCM as eluent togive2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(5.0 g, 9.8 mmol, 81% yield).

Step D:2-((S)-1-(but-2-ynoyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:At 0° C., to a 25 mL RBF containing N,N-dimethylformamide (1954 μl,0.391 mmol) was added2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(200 mg, 0.391 mmol) and triethylamine (136 μl, 0.977 mmol). Thereaction mixture was vigorously stirred while but-2-ynoic acid (49.3 mg,0.586 mmol) was added in one portion. 1-Propanephosphonic acid cyclicanhydride (175 μl, 0.293 mmol) was added slowly to the stirring mixture.The reaction was allowed to stir at it for 18 hr. Water was added andthe solids were filtered. The solids were purified by silica gel (5-18%MeOH in DCM with 0.25% NH4OH) to provide title compound2-((S)-1-(but-2-ynoyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(EXAMPLE 458, 110 mg, 0.190 mmol, 49% yield). ESI+APCI MS m/z 578.3[M+H]⁺.

Example 459

2-((S)-1-((E)-4-(dimethylamino)but-2-enoyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A:2-((S)-1-((E)-4-(dimethylamino)but-2-enoyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.A stirred mixture of2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(100 mg, 0.1954 mmol), (E)-4-(dimethylamino)but-2-enoic acid (37.86 mg,0.2932 mmol) and N,N-dimethylformamide (2 mL, 25.58 mmol) was cooled onice-salt bath and triethylamine (0.02724 mL, 0.1954 mmol) was added atonce, followed by 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane2,4,6-trioxide, 50% in EtOAc (0.1745 mL, 0.2932 mmol). The reactionmixture was allowed to warm to r.t. over 5 min, then stirred at r.t. for3 h. The reaction mixture was partitioned between EtOAc (50 mL) and 0.5M Na₂CO₃ (20 mL), the organics were separated, the organic layer waswashed with water and brine (10 mL each), dried over Na₂SO₄ andevaporated in vacuo. Chromatography on silica gel in 5 to 10% MeOH+0.5%NH₄OH in DCM afforded crude product that was purified on the reversephase, Gilson, 5 to 95% MeCN+0.1% TFA in water. The target fractionswere combined, basified with 2M Na₂CO₃ and extracted with DCM (3*20 mL).The combined extracts were washed with brine (10 mL), dried over Na₂SO₄and evaporated in vacuo. The solid residue was dissolved in DCM (3 mL),filtered and evaporated to yield the desired title compound as colorlesssolid (EXAMPLE 459, 40 mg, 33%). ESI+APCI MS m/z 623.3 [M+H]⁺.

Example 460

2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-morpholinobut-2-enoyl]piperazin-2-yl]acetonitrile

Step A: benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(Intermediate 65, 500 mg, 989 umol, 1.0 eq), Pd₂(dba)₃ (181 mg, 198umol, 0.20 eq), Xantphos (172 mg, 297 umol, 0.30 eq) and Cs₂CO₃ (967 mg,2.97 mmol, 3.0 eq) in toluene (5.0 mL) was added1-bromo-8-methyl-naphthalene (Intermediate 69, 284 mg, 1.29 mmol, 1.30eq). The mixture was stirred at 90° C. for 12 hours. After completion,the reaction mixture was added water (10.0 mL) and extracted with ethylacetate (10.0 mL×4). The organic layer was dried over Na₂SO₄, filteredand concentrated under vacuum. The residue was purified by reversedphase flash column (C18, 0.1% in formic acid, 0-70% acetonitrile) togive the product benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(400 mg, 619 umol, 63% yield) as yellow oil. LCMS [ESI, M+1]: 646.

Step B:2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(700 mg, 1.08 mmol, 1.0 eq) and NH₃·MeOH (20.0 mL, 30% purity) inmethanol (20.0 mL) was added Pd/C (200 mg, 10% purity). The mixture waspurged by nitrogen for 3 times. Then the mixture was stirred underhydrogen atmosphere (15 Psi) at 25° C. for 1 hour. After completion, thereaction mixture was filtered through celite, the filter cake was washedwith tetrahydrofuran (20.0 mL). The mother liquor was collected andconcentrated under vacuum to give the product2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(500 mg, 977 umol, 90% yield) as yellow oil.

¹H NMR (400 MHz, Chloroform-d) δ 7.70 (d, J=8.0 Hz, 1H), 7.64 (dd,J=3.2, 7.2 Hz, 1H), 7.43-7.37 (m, 1H), 7.34 (t, J=7.6 Hz, 1H), 7.26-7.19(m, 2H), 4.43-4.33 (m, 1H), 4.22 (dd, J=6.8, 18.0 Hz, 1H), 4.17-4.08 (m,1H), 4.07-3.89 (m, 1H), 3.89-3.70 (m, 2H), 3.52-3.45 (m, 2H), 3.38-3.20(m, 1H), 3.19-3.04 (m, 4H), 3.03-2.94 (m, 2H), 2.93-2.82 (m, 4H),2.70-2.60 (m, 1H), 2.60-2.49 (m, 3H), 2.47 (d, J=2.4 Hz, 3H), 2.31-2.22(m, 1H), 2.11-2.00 (m, 1H), 1.88-1.76 (m, 3H).

Step C:2-[(2S)-1-[(E)-4-bromobut-2-enoyl]-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(250 mg, 489 umol, 1.0 eq) and pyridine (309 mg, 3.91 mmol, 316 uL, 8.0eq) in dichloromethane (4.0 mL) was added (E)-4-bromobut-2-enoylchloride (359 mg, 1.95 mmol, 4.0 eq). The mixture was stirred at 0° C.for 0.5 hour. After completion, the reaction mixture was concentrated togive the product2-[(2S)-1-[(E)-4-bromobut-2-enoyl]-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(330 mg, crude) as yellow oil. The product was used for the next stepwithout further purification. LCMS [ESI, M+1]: 658.

Step D:2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-morpholinobut-2-enoyl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-1-[(E)-4-bromobut-2-enoyl]-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(300 mg, crude) and K₂CO₃ (630 mg, 4.55 mmol, 10.0 eq) indichloromethane (2.0 mL) was added morpholine (238 mg, 2.73 mmol, 241uL, 6.0 eq). The mixture was stirred at 0° C. for 12 hours. Aftercompletion, the reaction mixture was added water (10.0 mL) and extractedwith ethyl acetate (10.0 mL×3). The organic layer was dried over Na₂SO₄,filtered and concentrated under vacuum. The residue was purified byprep-HPLC (column: Gemini 150*25 5 u; mobile phase: [water (0.05%ammonia hydroxide v/v)-ACN]; B %: 50%-80%, 12 min) to give the titlecompound2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-morpholinobut-2-enoyl]piperazin-2-yl]acetonitrile(EXAMPLE 460, 48.2 mg, 72.5 umol, 16% yield) as white solid. LCMS [ESI,M+1]: 665.

¹H NMR (400 MHz, Chloroform-d) δ 7.70 (br d, J=8.4 Hz, 1H), 7.65 (t,J=8.4 Hz, 1H), 7.41 (dd, J=7.6, 15.2 Hz 1H), 7.35 (t, J=7.6 Hz, 1H),7.27-7.17 (m, 2H), 7.02-6.91 (m, 1H), 6.55-6.39 (m, 1H), 5.23-4.47 (m,1H), 4.40-4.33 (m, 1H), 4.31-4.19 (m, 1H), 4.19-4.09 (m, 2H), 4.07-3.83(m, 2H), 3.81-3.64 (m, 5H), 3.59-3.40 (m, 2H), 3.24-3.13 (m, 4H),3.12-2.94 (m, 3H), 2.92 (s, 3H), 2.86-2.76 (m, 1H), 2.75-2.54 (m, 3H),2.50 (br s, 4H), 2.48-2.45 (m, 3H), 2.33-2.22 (m, 1H), 2.10-2.00 (m,1H), 1.87-1.71 (m, 3H).

Example 461

2-[(2R)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: tert-butyl4-[4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate.To a solution of tert-butyl2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (3 g,9.86 mmol, 1 eq) in DMAc (60 mL) was added DIEA (3.82 g, 29.6 mmol, 5.15mL, 3 eq) and 2-piperazin-2-ylacetonitrile (Intermediate 62, 2.15 g,10.9 mmol, 1.1 eq, 2HCl) at 0° C. The mixture was stirred at 25° C. for1.5 hrs. Then to the solution was added DIEA (2.55 g, 19.7 mmol, 3.43mL, 2 eq) and benzyl chloroformate (2.52 g, 14.8 mmol, 2.10 mL, 1.5 eq)at 0° C. The mixture was stirred at 25° C. for another 2.5 hrs. To thereaction mixture was added H₂O (40 mL) and ethyl acetate (100 mL). Theseparated organic phase was washed with 5% of aqueous citric acidsolution (40 mL×1), aqueous saturated Na₂CO₃ solution (40 mL×1) andbrine (40 mL×1), dried over sodium sulfate and filtered. The filtratewas concentrated under reduced pressure to give a residue. The residuewas triturated with methyl tert-butyl ether (25 mL) to give a pureproduct. tert-butyl4-[4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(4.10 g, 7.62 mmol, 79% yield, 98% purity) was obtained as a whitesolid. LCMS [ESI, M+1]: 527.

¹H NMR (400 MHz, chloroform-d) δ=7.43-7.29 (m, 5H), 5.17 (s, 2H),4.71-4.55 (m, 2H), 4.48-4.37 (m, 1H), 4.21-3.97 (m, 2H), 3.92-3.67 (m,2H), 3.40-3.20 (m, 3H), 3.09 (dt, J=3.6, 12.4 Hz, 1H), 2.88-2.57 (m,4H), 1.47 (s, 9H).

SFC condition (40935): Column: Chiralcel OD-3 50×4.6 mm I.D., 3 umMobile phase: methanol (0.05% DEA) in CO₂ from 5% to 40%. Flow rate: 3mL/min, Wavelength: 220 nm.

Step B: tert-butyl 4-[(3R)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate.tert-Butyl4-[4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(2.20 g, 4.17 mmol, 1 eq) was separated by SFC (column: OD (250 mm*30mm, 10 um); mobile phase: [0.1% NH₃H₂O MeOH]; B %: 40%-40%, 3.1 min: 180min). The desired fractions were collected and concentrated under vacuumto give tert-butyl 4-[(3R)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(940 mg, 1.78 mmol, 43% yield, 99.7% purity) as a white solid. LCMS[ESI, M+1]: 527.

SFC condition: Column: Chiralcel OD-3 50×4.6 mm I.D., 3 um, Mobilephase: methanol (0.05% DEA) in CO₂ from 5% to 40%, Flow rate: 3 mL/min,Wavelength: 220 nm.

Step C: tert-Butyl4-[(3R)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate.To a mixture of tert-butyl4-[(3R)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(290 mg, 550 umol, 1 eq), [(2S)-1-methylpyrrolidin-2-yl]methanol (127mg, 1.10 mmol, 131 uL, 2 eq), Pd₂(dba)₃ (60.5 mg, 66.0 umol, 0.12 eq),RuPhos (51.4 mg, 110 umol, 0.2 eq) and Cs₂CO₃ (448 mg, 1.38 mmol, 2.5eq) in toluene (20 mL) was degassed and purged with N₂ for 3 times, andthen the mixture was stirred at 90° C. for 7 hours under N₂ atmosphere.To the reaction mixture was added H₂O (25 mL×1) and ethyl acetate (25mL×2). The separated organic phase was washed with brine (100 mL×1),dried over sodium sulfate and then filtered. The filtrate wasconcentrated under reduced pressure. The residue was diluted with ethylacetate (50 mL) and acidified with aqueous HCl solution (1 mol/L) topH=3˜4. To the separated water layer was added ethyl acetate (60 mL) andbasified with saturated aqueous Na₂CO₃ solution to pH=8˜9. The organicphase was separated, dried over sodium sulfate, filtered andconcentrated under reduced pressure to give a residue. tert-Butyl4-[(3R)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(225 mg, 0.36 mmol, 66% yield, 97.7% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 606.

¹H NMR (400 MHz, chloroform-d) δ=7.47-7.30 (m, 5H), 5.19 (s, 2H),4.73-4.52 (m, 2H), 4.44-4.26 (m, 2H), 4.22-4.14 (m, 1H), 4.03-3.74 (m,3H), 3.41-3.21 (m, 3H), 3.08 (br t, J=7.6 Hz, 1H), 2.97 (dt, J=3.6, 12.4Hz, 1H), 2.89-2.53 (m, 5H), 2.46 (s, 3H), 2.38-2.10 (m, 2H), 2.08-2.03(m, 1H), 1.89-1.65 (m, 3H), 1.48 (s, 9H).

SFC condition: Column: Chiralpak AD-3 50×4.6 mm I.D., 3 um, Mobilephase: methanol (0.05% DEA) in CO2 from 5% to 40%, Flow rate: 3 mL/min,Wavelength: 220 nm.

Step D: benzyl(2R)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of tert-butyl4-[(3R)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(620 mg, 1.02 mmol, 1 eq) in dioxane (12 mL) was added HCl/dioxane (4 M,12.4 mL, 48.5 eq) at 0° C. The mixture was stirred at 25° C. for 0.5 h.The liquid was decanted and the residue was concentrated under vacuum.Benzyl(2R)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(470 mg, crude, HCl) was obtained as a yellow oil which was dissolvedinto DCM (10 mL). The mixture basified with saturated aqueous sodiumcarbonate solution to pH 9. The organic phase was separated, washed withbrine (5 mL×1), filtered and concentrated under reduced pressure to givea residue which was pure enough without further purification. Benzyl(2R)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(400 mg, 718 umol, 77% yield, 90.8% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 506.

Step E: benzyl(2R)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a mixture of benzyl(2R)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(210 mg, 415 umol, 1 eq), 1-bromo-8-methyl-naphthalene (Intermediate 69,119 mg, 540 umol, 1.3 eq) Pd₂(dba)₃ (76.1 mg, 83.1 umol, 0.2 eq), Cs₂CO₃(406 mg, 1.25 mmol, 3 eq) and Xantphos (72.1 mg, 125 umol, 0.3 eq) intoluene (7 mL) was degassed and purged with N₂ for 3 times, and then themixture was stirred at 90° C. for 8 hours under N₂ atmosphere. To thereaction mixture was added H₂O (20 mL×1) and the mixture was extractedwith ethyl acetate (20 mL×2). The extracts were dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas diluted with ethyl acetate (50 mL) and acidified to pH=3˜4 withaqueous HCl solution (1 mol/L). To the water layer was added ethylacetate (60 mL) and basified to pH=8˜9 with saturated aqueous Na₂CO₃solution. The organic phase was separated, dried over sodium sulfate,filtered and the filtrate was concentrated under reduced pressure. Theresidue was purified by column chromatography (SiO₂, ethylacetate/methanol 50/1 to 5/1). Benzyl(2R)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(86 mg, 0.128 mmol, 31% yield, 96.0 purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 646.

Step E:2-[(2R)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of benzyl(2R)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(130 mg, 201 umol, 1 eq) in MeOH (15 mL) was added Pd/C (25 mg, 15.5umol, 10% purity) and NH₃·MeOH (15.5 umol, 15 mL, 20% purity) under N₂.The suspension was degassed under vacuum and purged with HE for severaltimes. The mixture was stirred under H₂ (15 psi) at 25° C. for 1 hour.The catalyst was filtered off through a pad of celite. The filtrate wasconcentrated under vacuum.2-[(2R)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(100 mg, 0.183 mmol, 91% yield, 93.5% purity) was obtained as a yellowsolid and used into next step without further purification. LCMS [ESI,M+1]: 512.

Step F:2-[(2R)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a mixture of2-[(2R)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(100 mg, 195 umol, 1 eq) and TEA (198 mg, 1.95 mmol, 272 uL, 10 eq) inDCM (10 mL) was added prop-2-enoyl chloride (17.7 mg, 195 umol, 15.9 uL,1 eq) in portion. After stirring at −40° C. for 30 min, the mixture wasquenched with MeOH (2 mL) and concentrated under vacuum. The residue waspurified by column chromatography (Al₂O₃, Dichloromethane/Methanol=10/1to 10/1). The residue was purified by prep-HPLC (column: Luna C18 150*255 u; mobile phase: [water (0.225% FA)-ACN]; B %: 25%-45%, 7.8 min) and(column: Gemini 150*25 5 u; mobile phase: [water (0.05% ammoniahydroxide v/v)-ACN]; B %: 57%-87%, 12 min). The desired fractions wereconcentrated under reduced pressure to remove acetonitrile, and thenlyophlizated. Title compound2-[(2R)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 461, 17.6 mg, 31.0 umol, 16% yield, 100% purity) was obtainedas a white solid. LCMS [ESI, M+1]: 566.

SFC condition: Column: Chiralcel OJ-3 50×4.6 mm I.D., 3 um, Mobilephase: methanol (0.05% DEA) in CO₂ from 5% to 40%, Flow rate: 3 mL/min,Wavelength: 220 nm.

¹H NMR (400 MHz, chloroform-d) δ=7.77-7.63 (m, 2H), 7.48-7.32 (m, 2H),7.31-7.18 (m, 2H), 6.61 (br s, 1H), 6.48-6.37 (m, 1H), 5.85 (br d,J=10.0 Hz, 1H), 5.27-4.49 (m, 1H), 4.45-4.33 (m, 1H), 4.33-4.06 (m, 4H),4.05-3.62 (m, 3H), 3.61-3.34 (m, 2H), 3.33-2.99 (m, 5H), 2.94 (s, 3H),2.88-2.77 (m, 1H), 2.75-2.57 (m, 2H), 2.54-2.44 (m, 3H), 2.30 (br d,J=7.2 Hz, 1H), 2.15-1.95 (m, 1H), 1.95-1.79 (m, 3H).

Example 462

2-[(2S)-4-[7-(5,6-dimethyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: tert-butyl(2S)-2-(cyanomethyl)-4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.A mixture of tert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(600 mg, 1.27 mmol, 1 eq),4-bromo-5,6-dimethyl-1-tetrahydropyran-2-yl-indazole (511 mg, 1.65 mmol,1.3 eq), RuPhos (237 mg, 509 umol, 0.4 eq), Cs₂CO₃ (1.04 g, 3.18 mmol,2.5 eq) and Pd₂(dba)₃ (233 mg, 254 umol, 0.2 eq) in toluene (20 mL) wasde-gassed and then heated to 90° C. for 8 hours under N₂. Uponcompletion, the mixture was filtered and the filtrate was concentratedunder vacuum. The residue was purified by reversed phase flash [water(0.1% FA)/acetonitrile]. The desired fractions were collected andneutralized with saturated aqueous NaHCO₃. The mixture was concentratedunder vacuum to remove MeCN and extracted with EtOAc (2×50 mL). Theorganic layers were washed with brine (50 mL), dried over Na₂SO₄,filtered and concentrated under vacuum to give tert-butyl(2S)-2-(cyanomethyl)-4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(365 mg, 469 umol, 37% yield, 90% purity) as a yellow solid. LCMS [ESI,M+1]: 700.

¹H NMR (400 MHz, chloroform-d) δ=7.99 (s, 1H), 7.22 (s, 1H), 5.66 (dd,J=2.8, 9.6 Hz, 1H), 4.61 (br s, 1H), 4.40 (br dd, J=4.8, 10.4 Hz, 1H),4.26 (br s, 2H), 4.09-3.97 (m, 3H), 3.90 (br d, J=11.6 Hz, 1H),3.80-3.71 (m, 1H), 3.50 (br t, J=4.8 Hz, 2H), 3.25 (br s, 2H), 3.09 (brt, J=7.6 Hz, 1H), 2.99 (br t, J=11.2 Hz, 1H), 2.83-2.51 (m, 6H), 2.48(s, 3H), 2.43 (s, 3H), 2.33 (s, 3H), 2.31-2.24 (m, 1H), 2.21-2.13 (m,1H), 2.11-2.06 (m, 1H), 1.90-1.69 (m, 8H), 1.52 (s, 9H).

Step B:2-[(2S)-4-[7-(5,6-dimethyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-2-(cyanomethyl)-4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(720 mg, 1.03 mmol, 1 eq) in DCM (1 mL) was added TFA (4.62 g, 40.5mmol, 3 mL, 39.4 eq). The mixture was stirred at 20° C. for 4 hours.Upon completion, the mixture was diluted with DCM (10 mL) andneutralized with saturated aqueous NaHCO₃. Then the aqueous phase wasextracted with EtOAc (2×30 mL). The organic layers were combined, driedover Na₂SO₄, filtered and concentrated under vacuum to give2-[(2S)-4-[7-(5,6-dimethyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(880 mg, crude) as a yellow solid which was used directly in the nextstep without further purification. LCMS [ESI, M+1]: 516.

Step C:(2-[(2S)-4-[7-(5,6-dimethyl-1H-indazol-4-yl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(5,6-dimethyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(150 mg, crude) and TEA (177 mg, 1.75 mmol, 243 uL) in DCM (4 mL) wasadded prop-2-enoyl chloride (13.2 mg, 145 umol, 11.9 uL) dropwise at−40° C. After stirring at −40° C. for 30 minutes, the mixture wasquenched with saturated aqueous NaHCO₃ (1 mL) and extracted with DCM(2×10 mL). The organic layers were dried over Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by chromatography(Al₂O₃, EtOAc/MeOH 1/0 to 10/1) followed by prep-HPLC (column: Gemini200*30 10μ: mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B %: 40%-70%, 6.0min). The desired fractions were collected and lyophilized to give titlecompound(2-[(2S)-4-[7-(5,6-dimethyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(EXAMPLE 462, 15.6 mg, 27.2 umol, two steps 15% yield, 99.6% purity) asa white solid. LCMS [ESI, M+1]: 570.

SFC condition: Column: Chiralcel OJ-3 100×4.6 mm I.D., 3 um, Mobilephase: methanol (0.05% DEA) in CO₂ from 5% to 40%, Flow rate: 3 mL/min,Wavelength: 220 nm.

¹H NMR (400 MHz, chloroform-d) δ=10.26 (br s, 1H), 8.03 (s, 1H), 7.14(s, 1H), 6.57 (br d, J=9.6 Hz, 1H), 6.39 (dd, J=1.2, 16.4 Hz, 1H), 5.83(br d, J=10.4 Hz, 1H), 5.12-4.38 (m, 2H), 4.28 (s, 2H), 4.23-3.84 (m,4H), 3.73-3.40 (m, 3H), 3.32 (br s, 1H), 3.10 (br t, J=7.6 Hz, 2H),2.98-2.61 (m, 5H), 2.48 (s, 3H), 2.41 (s, 3H), 2.34 (s, 3H), 2.32-2.24(m, 1H), 2.11-1.99 (m, 1H), 1.91-1.78 (m, 3H).

Example 463

(S,E)-3-((4-(3-(cyanomethyl)-4-(4-(dimethylamino)but-2-enoyl)piperazin-1-yl)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)-N,N-dimethylpropanamide

Step A: tert-butyl(S)-4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate-Benzyl(S)-2-(cyanomethyl)piperazine-1-carboxylate hydrochloride (10 g, 34mmol) was dissolved in DMA (68 ml, 34 mmol). To the solution was nextadded tert-butyl2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (9.3g, 30 mmol) followed by Hunig's Base (24 ml, 135 mmol) and the reactionstirred at room temperature for 1 hour. The reaction was next pouredinto basic water and extracted with MTBE. The organics were washed withadditional water, brine, dried over Na₂ SO₄ and concentrated in vacuo.The concentrate was then chromatographed using 10→70% EtOAc/Hexane aseluent to give tert-butyl(S)-4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(12 g, 67% yield). ESI+APCI MS m/z 580.3 [M+H]⁺.

Step B: benzyl(S)-4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:Tert-butyl(S)-4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(1.5 g, 2.8 mmol) was dissolved in DCM (28 ml, 2.8 mmol) and treatedwith Hydrochloric Acid Solution (4.0 M in 1,4-dioxane)(3.6 ml, 14 mmol).The reaction was stirred at room temperature for 1 hour. The organicswere washed with 1M NaOH. The aqueous layer was extracted with DCM (2×).The combined organics were dried over Na₂ SO₄, concentrated in vacuo andtaken forward as crude benzyl(S)-4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(1.2 g, 99% yield). ESI+APCI MS m/z 427.2 [M+H]⁺.

Step C: benzyl(S)-4-(2-chloro-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:Tris(dibenzylideneacetone)dipalladium(0) (0.51 g, 0.56 mmol) andXantphos (0.54 g, 1.1 mmol) were dissolved in 1,4-dioxane (28 ml, 2.8mmol) and purged under Argon for 5 minutes followed by stirring at 100°C. under Argon for 15 minutes. The reaction was next cooled to roomtemperature. To the reaction was added benzyl(S)-4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(1.2 g, 2.8 mmol), 1-bromo-8-methylnaphthalene (1.9 g, 8.4 mmol), andCesium Carbonate (2.7 g, 8.4 mmol) under Argon. The reaction was cappedunder Argon and stirred at 100° C. over night. The reaction was cooledto room temperature and was filtered through GF/F paper. The filtratewas concentrated in vacuo and purified by normal phase chromatography onthe CombiFlash using 0%→75% Hexanes/EtOAc as the eluent to give benzyl(S)-4-(2-chloro-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(0.45 g, 28% yield). ESI+APCI MS m/z 567.2 [M+H]⁺.

Step D: benzyl(S)-2-(cyanomethyl)-4-(2-(3-(dimethylamino)-3-oxopropoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,4-dihydropyrazine-1(2H)-carboxylate:In a microwave tube a solution of benzyl(S)-4-(2-chloro-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(250 mg, 0.441 mmol) in dioxane (4408 μl, 0.441 mmol) was sparged withArgon for 5 minutes. 3-Hydroxy-N,N-dimethylpropanamide (155 mg, 1.32mmol), Cesium Carbonate (431 mg, 1.32 mmol),Methanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II)(37.5 mg, 0.0441 mmol) were sequentially added under Argon and thereaction sparged for an additional 5 minutes with Argon. The reactionmixture was capped and heated at 100° C. for 1 hour. The reaction wascooled to room temperature and Ethyl Acetate was added. The reaction wasfiltered through GF/F paper and the filtrated concentrated in vacuo. Theresidue was purified by flash chromatography eluting with 0→20% MeOH+2%NH₄OH/DCM. All fractions containing clean desired product were combinedand concentrated to give benzyl(S)-2-(cyanomethyl)-4-(2-(3-(dimethylamino)-3-oxopropoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,4-dihydropyrazine-1(2H)-carboxylate(140 mg, 49.2% yield). ESI+APCI MS m/z 648.3 [M+H]⁺.

Step E:(S)-3-((4-(3-(cyanomethyl)piperazin-1-yl)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)-N,N-dimethylpropanamide:A solution of benzyl(S)-2-(cyanomethyl)-4-(2-(3-(dimethylamino)-3-oxopropoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(140 mg, 0.216 mmol) in EtOH (2161 μl, 0.216 mmol) and THF (2161 μl,0.216 mmol) was purged with N₂ for 5 minutes. To this solution was addedPalladium (57.5 mg, 0.0540 mmol) (Degussa Type, 10 wt %, 50% H2O) andthe reaction capped and purged with N₂ for an additional 5 minutes. Thesolution was stirred under one atmosphere of H₂ overnight. The mixturewas diluted with MeOH and filtered through packed celite. The filtratewas then concentrated in vacuo to provide crude(S)-3-((4-(3-(cyanomethyl)piperazin-1-yl)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)-N,N-dimethylpropanamide(111 mg, 100.0% yield). ESI+APCI MS m/z 514.3 [M+H]⁺.

Step F:(S,E)-3-((4-(3-(cyanomethyl)-4-(4-(dimethylamino)but-2-enoyl)piperazin-1-yl)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)-N,N-dimethylpropanamide.To a 25 mL round bottom flask containing dichloromethane (2161 μl, 0.216mmol) cooled to 0° C. was added(S)-3-((4-(3-(cyanomethyl)piperazin-1-yl)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)-N,N-dimethylpropanamide(111 mg, 0.216 mmol) and Hunig's base (226 μl, 1.30 mmol). The reactionmixture was vigorously stirred while (E)-4-(dimethylamino)but-2-enoicacid (167 mg, 1.30 mmol) was added in one portion. Next,1-Propanephosphonic acid cyclic anhydride (772 μl, 1.30 mmol) was addedslowly to the stirring mixture. The reaction was stirred for 2 hours at0° C. The reaction was treated with basic water and the aqueous layerextracted with EtOAc (3×). The combined organics were concentrated invacuo and purified on the Gilson (prep HPLC) eluting with 5→95% ACN+0.1%TFA/water+0.1% TFA. Fractions containing product were combined, dilutedwith 1M NaOH and the aqueous layer extracted with DCM. The organics weredried over Na₂ SO₄ and concentrated in vacuo to give title compound(S,E)-3-((4-(3-(cyanomethyl)-4-(4-(dimethylamino)but-2-enoyl)piperazin-1-yl)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)-N,N-dimethylpropanamide(17.6 mg, 13.0% yield) ESI+APCI MS m/z 625.4 [M+H]⁺.

Example 464

2-((S)-1-acryloyl-4-(7-(8-bromonaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: Benzyl(S)-4-(7-(8-bromonaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:Benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(200 mg, 0.396 mmol), Cs₂CO₃ (644 mg, 1.98 mmol), 1,8-dibromonaphthalene(339 mg, 1.19 mmol), Pd₂(dba)₃ (72.4 mg, 0.0791 mmol) and XANTPHOS (91.6mg, 0.158 mmol) were diluted with toluene (1582 μl, 0.396 mmol). Thereaction was purged with argon, sealed and heated to 100° C. Afterstirring for 23 hours, the reaction was cooled and diluted with ethylacetate and saturated sodium bicarbonate. The layers were separated andthe ethyl acetate was dried over MgSO₄, filtered and concentrated. Thematerial was purified on silica gel eluting with 1-10% methanol/DCM (1%NH4OH as additive) to afford benzyl(S)-4-(7-(8-bromonaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(68 mg, 24.2% yield). ESI+APCI MS m/z 712.2 [M+H]⁺.

Step B:2-((S)-4-(7-(8-bromonaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:Benzyl(S)-4-(7-(8-bromonaphthalen-1-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(25 mg, 0.035 mmol) was diluted with TFA (2 mL), placed under nitrogenand heated to 90° C. After stirring for 2 hours, the reaction was cooledand concentrated. The material was diluted with DCM and washed withsaturated sodium bicarbonate. The DCM was dried over MgSO₄, filtered andconcentrated. The material was purified on silica gel eluting with 10%methanol/DCM (1% NH4OH as additive) to afford2-((S)-4-(7-(8-bromonaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(8 mg, 39% yield). ESI−APCI MS m/z 578.2 [M+H]⁺.

Step C:2-((S)-1-acryloyl-4-(7-(8-bromonaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:2-((S)-4-(7-(8-bromonaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(8 mg, 0.014 mmol) was diluted with DCM (200 uL) followed by theaddition of acryloyl chloride (1.4 mg, 0.015 mmol) and DIEA (4.8 μl,0.028 mmol). After stirring for 12 hours, the reaction was diluted withsaturated sodium carbonate and extracted twice with DCM. The DCM wasdried over MgSO₄, filtered and concentrated. The material was purifiedon silica gel eluting with 10% methanol/DCM (1% NH4OH as additive) toafford title compound2-((S)-1-acryloyl-4-(7-(8-bromonaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(EXAMPLE 464.6 mg, 69% yield). ESI+APCI MS m/z 632.2 [M+H]⁺.

Example 465

(R)-4-acryloyl-1-(2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-2-carbonitrile

Step A: benzyl(R)-4-(4-(tert-butoxycarbonyl)-2-cyanopiperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:A mixture of benzyl2,4-dichloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (700mg, 2.07 mmol), R-1-N-Boc-3-cyanopiperazine (656 mg, 3.10 mmol),N,N-dimethylacetamide (1 ml) and N-ethyl-N-isopropylpropan-2-amine(0.433 ml, 2.48 mmol) was stirred at 60° C. under nitrogen atmospherefor 48 hours. The reaction mixture was cooled, partitioned between MTBE(50 mL) and 0.2M Na₂CO₃ (15 mL) and the layers separated. The organiclayer was washed with water and brine (10 mL each), dried over Na₂SO₄and evaporated in vacuo. The material crystallized upon dilution withMTBE (5 mL). The mother liquor was decanted and the solid was washedwith MTBE (2*1 mL) followed by purification on silica gel using in 40 to60% EtOAc/hexane as eluent to give product (308 mg, 29%) ESI+APCI MS m/z513.2 [M+H]⁺.

Step B: benzyl4-((R)-4-(tert-butoxycarbonyl)-2-cyanopiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:A mixture of benzyl(R)-4-(4-(tert-butoxycarbonyl)-2-cyanopiperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(308 mg, 0.600 mmol), Cs₂CO₃ (587 mg, 1.80 mmol),methanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II)(RuPhos-Pd-G4, 51.1 mg, 0.0600 mmol),(S)-(1-methylpyrrolidin-2-yl)methanol (346 mg, 3.00 mmol) and1,4-dioxane (4 ml) was purged with N₂ and the vial was capped andreaction stirred at 70° C. for 2 hours. The reaction mixture waspartitioned between water (5 mL) and EtOAc (20 mL) and the organic layerseparated. The organics were washed with water and brine (3 mL each),dried over Na₂SO₄ and evaporated in vacuo. The residue waschromatographed on silica gel using 4% MeOH+0.4% NH₄OH/DCM as eluent togive product as a mixture of isomers (214 mg of ˜60% purity, 36%).ESI+APCI MS m/z 592.3 [M+H]⁺.

Step C: tert-butyl (R3-cyano-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:A mixture of crude benzyl4-((R)-4-(tert-butoxycarbonyl)-2-cyanopiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(214 mg, 0.362 mmol), methanol (7 ml, 0.362 mmol), and palladium oncarbon (20 mg, 5%, Degussa type E101 NO/W) was degassed and stirredunder hydrogen atmosphere for 1.5 hours. The reaction mixture wasfiltered through Celite (2 mL), the celite washed with MeOH (3*3 mL) andthe combined organics evaporated in vacuo to give product which was usedcrude in the next reaction. ESI+APCI MS m/z 458.3 [M+H]⁺.

Step D: tert-butyl(R)-3-cyano-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:A mixture of tert-butyl(R)-3-cyano-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(165 mg, 0.361 mmol), Cs₂CO₃ (352 mg, 1.08 mmol), dioxane (0.5 mL),1-iodonaphthalene (0.0790 ml, 0.541 mmol) andmethanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II)(RuPhos-Pd-G4, 0.1 eq., 30.7 mg, 0.0361 mmol) was purged with nitrogen,the flask capped and stirred at 70° C. for 1.5 hours. The reactionmixture was cooled and partitioned between EtOAc (20 mL) and water (5mL) and the layers separated. The organic layer was washed with waterand brine (5 mL each), dried over Na₂SO₄ and evaporated in vacuo. Theresidue was chromatographed on silica gel using 4% MeOH+0.4% NH₄OH/DCMas eluent to give product (120 mg, 57%). ESI+APCI MS m/z 584.3 [M+H]⁺.

Step E:(R)-1-(2-(((S)-1-methylpyrrolidin-2-yl)methoxyl-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-2-carbonitrile:The (tert-butyl(R)-3-cyano-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(120 mg, 0.206 mmol) was dissolved in dichloromethane (0.5 ml) andcooled to 0° C. followed by addition of 4M hydrogen chloride (1.03 ml,4.11 mmol) and the reaction stirred for 1 hr while warming to roomtemperature. The mixture was evaporated in vacuo and the residue waspartitioned between DCM (10 mL) and 2M Na₂CO₃ (0.5 mL) and the layersseparated. The organics were dried over Na₂CO₃, filtered and evaporatedin vacuo. The material was used crude in the next reaction. ESI+APCI MSm/z 484.2 [M+H]⁺.

Step F:(R)-4-acryloyl-1-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-2-carbonitrile:A solution of(R)-1-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-2-carbonitrile(79 mg, 0.1634 mmol) in DCM (5 mL) was cooled to −30° C. with stirringfollowed by addition of triethylamine (68.31 μl, 0.4901 mmol) andacryloyl chloride (26.54 μl, 0.3267 mmol). After 5 minutes at −30° C.,the reaction was quenched by addition of MeOH (0.05 mL) and the reactionwarmed to room temperature. The organics were next separated and washedwith 0.5M Na₂CO₃ (4 mL), dried over Na₂CO₃ and evaporated in vacuo. Theresidue was chromatographed on silica gel using 4% MeOH+0.4% NH₄OH/DCMas eluent to give title compound (EXAMPLE 465, 17 mg, 19%). ESI+APCI MSm/z 538.3 [M+H]⁺.

Example 466

2-((S)-1-acryloyl-4-(7-(5,6-dimethyl-1H-indol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-((S)-1-acryloyl-4-(7-(5,6-dimethyl-1H-indol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.The title compound is prepared following Example 454 substitutingIntermediate 66 for tert-butyl4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylatein Step A.

Example 467

2-((S)-1-acryloyl-4-(2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-((S)-1-acryloyl-4-(2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:The tide compound is prepared following Example 447 substituting benzyl(S)-4-(2-chloro-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylatein Example 447, Step A for benzyl(S)-4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylatein Example 447, Step A.

Example 468

2-((S)-1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-((S)-1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:The title compound is prepared following Example 447 substituting benzyl(S)-4-(2-chloro-7-(8-chloronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylatein Example 447, Step A for benzyl(S)-4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylatein Example 447, Step A.

Example 469

(S)-1-(4-(2-((4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6-dimethyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

(S)-1-(4-(2-((4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6-dimethyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one:The title compound is prepared following EXAMPLE 457 substitutingEXAMPLE 139, Step B product 2-(3,3-difluoropyrrolidin-1-yl)ethanol for[(2S)-1-methylpyrrolidin-2-yl]methanol in preparation of Intermediate66, Step E and then following EXAMPLE 457 Steps B-D.

Example 470

(S)-1-(4-(2-((4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6-dimethyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

(S)-1-(4-(2-((4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6-dimethyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one:The title compound is prepared following Example 453 substitutingExample 139, Step B product 2-(3,3-difluoropyrrolidin-1-yl)ethanol for[(2S)-1-methylpyrrolidin-2-yl]methanol in preparation of Intermediate66, Step E and then following Example 453 Steps B-C.

Example 471

2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-(3,3-difluoropyrrolidin-1-yl)but-2-enoyl]piperazin-2-yl]acetonitrile

(E)-4-bromobut-2-enoyl chloride. To a solution of (E)-4-bromobut-2-enoicacid (500 mg, 3.03 mmol, 1.0 eq) in DCM (2.0 mL) was added (COCl)₂ (4.35g, 34.3 mmol, 3.0 mL, 11.3 eq). The mixture was stirred at 60° C. for 12hours. The reaction mixture was concentrated under reduced pressure togive a residue. The crude product (E)-4-bromobut-2-enoyl chloride (500mg, crude) was obtained as brown oil.

Step A: tert-butyl(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.To a solution of tert-butyl(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(1.30 g, 2.17 mmol, 1.0 eq) and [(2S)-1-methylpyrrolidin-2-yl]methanol(500 mg, 4.34 mmol, 515 uL, 2.0 eq) in toluene (20.0 mL) was addedt-BuONa (417 mg, 4.34 mmol, 2.0 eq). The mixture was stirred at 0° C.for 10 min. The reaction mixture was quenched by addition saturatedbrine (30.0 mL) at 20° C., and extracted with EA (3×30.0 mL). Thecombined organic layer was washed with saturated brine (30.0 mL), thendried over Na₂SO₄, filtered and concentrated under reduced pressure togive a residue. The residue was purified by column chromatography (SiO2,Petroleum ether/Ethyl acetate=3/1 to EA/MeOH=10/1). The producttert-butyl(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(1.1 g, 1.62 mmol, 75% yield, 96% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 650.

Step B:2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(100 mg, 154 umol, 1.00 eq) in dioxane (0.5 mL) was added HCl·dioxane (4M, 1.00 mL, 26.0 eq). The mixture was stirred at 0° C. for 10 min. Thereaction mixture was concentrated under reduced pressure to removedioxane. The residue was diluted with saturated NaHCO₃ aqueous (10.0 mL)and extracted with EA (10 mL×3). The combined organic layers were washedwith saturated brine (20.0 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The crude product2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(90.0 mg, crude) was obtained as a white solid. LCMS [ESI, M+1]:550.

Step C:2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-(3,3-difluoropyrrolidin-1-yl)but-2-enoyl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(80.0 mg, 145 umol, 1.0 eq) in DCM (3.0 mL) was added Py (115 mg, 1.45mmol, 117 uL, 10.0 eq) and (E)-4-bromobut-2-enoyl chloride (107 mg, 582umol, 4.0 eq) in DCM (3.0 mL). The mixture was stirred at 0° C. for 1hour. After the starting material was consumed, then to a solution of3,3-difluoropyrrolidine (156 mg, 1.45 mmol, 10.0 eq) in DCM (6.0 mL) wasadded the reaction mixture. The mixture was stirred at 0° C. at 2 hours.The reaction mixture was concentrated under reduced pressure to give aresidue. The residue was purified by prep-HPLC (column: PhenomenexGemini 150*25 mm*10 um; mobile phase: [water (0.05% ammonia hydroxidev/v)-ACN]; B %: 62%-92%, 12 min). And the residue was concentrated underreduced pressure to remove ACN, and then lyophilization. Title compound2-[(2S)-4-[7-[3-chloro-2-(trifluoromethyl)phenyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-(3,3-difluoropyrrolidin-1-yl)but-2-enoyl]piperazin-2-yl]acetonitrile(EXAMPLE 471, 15.4 mg, 20.8 umol, 14% yield, 97.7% purity) was obtainedas a white solid. LCMS [ESI, M+1]: 723.

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.40 (t, J=8.2 Hz, 1H), 7.30-7.26 (m,1H), 7.19 (d, J=8.0 Hz, 1H), 7.05-6.90 (m, 1H), 6.60-6.40 (m, 1H), 5.08(br s, 1H), 4.39 (br dd, J=5.2, 10.8 Hz, 1H), 4.17 (br dd, J=6.8, 10.8Hz, 1H), 4.1 (br s, 2H), 4.12-4.05 (m, 1H), 3.97 (br d, J=10.8 Hz, 2H),3.70-3.53 (m, 1H), 3.35-3.25 (m, 3H), 3.17-3.07 (m, 2H), 2.96 (br t,J=13.2 Hz, 3H), 2.90-2.85 (m, 1H), 2.81 (br t, J=6.8 Hz, 3H), 2.75-2.65(m, 2H), 2.50 (s, 3H), 2.40-2.27 (m, 3H), 2.15-1.95 (m, 1H), 1.95-1.72(m, 5H).

Example 472

2-[(2S)-4-[7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile

2-chloroprop-2-enoyl chloride. To a solution of 2-fluoroprop-2-enoicacid (400 mg, 4.44 mmol, 1.0 eq) in DCM (1.50 mL) was added (COCl)₂ (846mg, 6.66 mmol, 583 uL, 1.50 eq) and DMF (32.5 mg, 444 umol, 34.2 uL,0.10 eq). The mixture was stirred at 25° C. for 2 hours.2-chloroprop-2-enoyl chloride (400 mg, crude) was used for the next stepdirectly.

Step A:2-[(2S)-4-[7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-2-(cyanomethyl)-4-[7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 347 umol, 1.0 eq) in DCM (2.0 mL) was added TFA (3.08 g, 27.0mmol, 2.0 mL, 77.8 eq). The mixture was stirred at 20° C. for 10 min.The reaction mixture was concentrated under reduced pressure to give aresidue. The product2-[(2S)-4-[7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(200 mg, crude, TFA) was obtained as a yellow solid and used into thenext step without further purification.

Step B:2-[(2S)-4-[7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(200 mg, 339 umol, 1.0 eq, TFA) in DCM (2.0 mL) was added DIEA (1.11 g,8.61 mmol, 1.50 mL, 25.4 eq) and 2-fluoroprop-2-enoyl chloride (200 mg,1.84 mmol, 5.43 eq) in DCM (2.0 mL). The mixture was stirred at 0° C.for 1 hour. The reaction mixture was concentrated under reduced pressureto give a residue. The residue was purified by prep-HPLC (column:Phenomenex Gemini 150*25 mm*10 um; mobile phase: [water (0.05% ammoniahydroxide v/v)-ACN]; B %: 55%-83%, 12 min). Title compound2-[(2S)-4-[7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile(EXAMPLE 472, 120 mg, 217 umol, two steps 62% yield, 98.9% purity) wasobtained as a yellow solid. LCMS [ESI, M+1]: 548.

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.11 (t, J=7.8 Hz, 1H), 7.01-6.91 (m,2H), 5.52-5.32 (m, 1H), 5.26 (dd, J=3.2, 16.8 Hz, 1H), 5.08-4.70 (br s,1H), 4.39 (dd, J=5.2, 10.4 Hz, 1H), 4.25-4.02 (m, 5H), 3.97 (d, J=12.8Hz, 1H), 3.43-3.73 (br s, 1H), 3.32 (d, J=13.2 Hz, 1H), 3.25-3.16 (m,1H), 3.15-3.02 (m, 3H), 3.01-2.91 (m, 1H), 2.90-2.80 (m, 2H) 2.79-2.60(m, 2H), 2.49 (s, 3H), 2.31-2.28 (m, 7H), 2.13-1.97 (m, 1H), 1.90-1.70(m, 3H).

Example 473

2-[(2S)-1-(2-chloroprop-2-enoyl)-4-[7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

2-chloroacryloyl chloride. A solution of 2-chloroprop-2-enoic acid (400mg, 3.76 mmol, 1.0 eq) and (COCl)₂ (715 mg, 5.63 mmol, 493 uL, 1.50 eq)in DCM (1.0 mL) was stirred at 25° C. for 0.5 hour. After completion,the reaction mixture was not work-up, and used for the next stepdirectly.

Step A:2-[(2S)-4-[7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-2-(cyanomethyl)-4-[7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(Intermediate 73, 400 mg, 695 umol, 1.0 eq) in DCM (0.50 mL) was addedTFA (3.08 g, 27.0 mmol, 2.0 mL, 38.9 eq). The mixture was stirred at 20°C. for 0.5 hour. After completion, the mixture was concentrated andadjusts with saturated NaHCO₃ aqueous to pH˜7, then extracted with DCM(5.0 mL×3). The organic layer was dried over Na₂SO₄, filtered andconcentrated. The product2-[(2S)-4-[7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(400 mg, crude) was obtained as yellow oil and used to the next stepwithout further purification.

Step B:2-[(2S)-1-(2-chloroprop-2-enoyl)-4-[7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(300 mg, 631 umol, 1.0 eq) and DIEA (245 mg, 1.89 mmol, 330 uL, 3.0 eq)in DCM (1.0 mL) was added 2-chloroprop-2-enoyl chloride (236 mg, 1.89mmol, 3.0 eq) at −78° C. The mixture was stirred at −78° C. for 0.5hour. After completion, the mixture was added saturated NaHCO₃ aqueous(2.0 mL) and extracted with EA (10.0 mL×3). The obtained product waspurified by prep-HPLC (column: Gemini 150*25 5 u; mobile phase: [water(0.05% ammonia hydroxide v/v)-ACN]; B %: 53%-83%, 12 min) to give titlecompound2-[(2S)-1-(2-chloroprop-2-enoyl)-4-[7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(EXAMPLE 473, 4.72 mg, 8.35 umol, two steps 1% yield, 99.8% purity) aswhite solid. LCMS [ESI, M+1]: 564.

¹H NMR (400 MHz, Chloroform-d) δ 7.11 (t, J=7.8 Hz, 1H), 6.98-6.94 (m,2H), 5.86-5.78 (m, 1H), 5.77-5.72 (m, 1H), 5.15-4.78 (m, 1H), 4.45-4.30(m, 1H), 4.21-4.12 (m, 1H), 4.10-4.03 (m, 3H), 3.96 (br d, J=12.4 Hz,2H), 3.30 (br dd, J=3.2, 13.6 Hz, 1H), 3.23-3.04 (m, 41H), 3.04-2.54 (m,6H), 2.50 (br s, 3H), 2.34-2.23 (m, 7H), 2.12-2.02 (m, 1H), 1.91-1.66(m, 3H).

Example 474

2-((S)-1-(4-hydroxybut-2-ynoyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl))methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a mixture of benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(Intermediate 65, 1 g, 1.58 mmol, 1 eq) and 1-bromonaphthalene (655 mg,3.16 mmol, 440 uL, 2 eq) in toluene (20 mL) was added Pd₂(dba)₃ (145 mg,158 umol, 0.1 eq), RuPhos (148 mg, 316 umol, 0.2 eq), Cs₂CO₃ (1.55 g,4.75 mmol, 3 eq) in one portion. The mixture was degassed and purgedwith N₂ for 3 times, then heated to 90° C. and stirred for 2 hours. Thereaction mixture was diluted with water (15 mL) and extracted with ethylacetate (50 mL×3). The combined organic layers were washed with water(50 mL×1), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue. The residue was purified by reversed phaseflash [water (0.1% TFA)/acetonitrile]. The desired fractions werecollected and neutralized with saturated NaHCO₃ solution (6 mL) andextracted with ethyl acetate (100 mL×2). The separated organic layerswere dried over sodium sulfate, filtered and concentrated under vacuum.Compound benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(515 mg, 726 umol, 45.9% yield, 89.1% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 632.

Step B:2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1 g, 1.58 mmol, 1 eq) in MeOH (60 mL) was added Pd/C (500 mg, 10%purity) and NH₃·MeOH (20%, 50 mL) under N₂. The suspension was degassedunder vacuum and purged with H₂ three times. The mixture was stirredunder H₂ (15 psi) at 25° C. for 1 hour. The reaction mixture wasconcentrated under reduced pressure. Compound2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(680 mg, 1.26 mmol, 80% yield, 92.3% purity) was obtained as a yellowsolid which was used directly into the next step without furtherpurification. LCMS [ESI, M+1]: 498.

¹H NMR (400 MHz, chloroform-d) δ=8.26-8.19 (m, 1H), 7.89-7.83 (m, 1H),7.60 (d, J=8.4 Hz, 1H), 7.53-7.47 (m, 2H), 7.43 (t, J=7.6 Hz, 1H),7.16-7.12 (m, 1H), 4.41 (dd, J=5.2, 10.8 Hz, 1H), 4.26 (s, 2H), 4.16(dd, J=7.2, 10.8 Hz, 1H), 4.01 (br d, J=12.4 Hz, 1H), 3.95-3.82 (m, 1H),3.44-3.21 (m, 3H), 3.18-2.97 (m, 4H), 2.95-2.76 (m, 3H), 2.74-2.63 (m,1H), 2.55 (dd, J=1.2, 5.6 Hz, 2H), 2.51-2.46 (m, 3H), 2.33-2.22 (m, 1H),2.12-1.99 (m, 1H), 1.88-1.80 (m, 3H).

Step C:2-[(2S)-1-(4-hydroxybut-2-ynoyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of 4-[tert-butyl(dimethyl)silyl]oxybut-2-ynoic acid (172mg, 803 umol, 2 eq) and DIEA (155 mg, 1.21 mmol, 210 uL, 3 eq) in MeCN(5 mL) was added MsCl (92.1 mg, 803 umol, 62.2 uL, 2 eq) at 0° C. Afterstirring at 0° C. for 20 minutes, to the mixture was added2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(200 mg, 402 umol, 1 eq) and the mixture was stirred at 25° C. for 2hours. Then the reaction mixture was heated to 80° C. and stirred for 10hours. The reaction mixture was diluted with water (20 mL) and extractedwith ethyl acetate (20 mL×3). The combined organic layers were washedwith brine (20 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified byprep-HPLC (column: Boston Green ODS 150*30 5 u; mobile phase: [water(0.225% FA)-ACN]. B %: 25%-45%, 10 min) and further purified byprep-HPLC (column: Phenomenex Gemini 150*25 mm*10 um; mobile phase:[water (0.05% ammonia hydroxide v/v)-ACN]; B %: 45%-75%, 12 min). Titlecompound2-[(2S)-1-(4-hydroxybut-2-ynoyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(EXAMPLE 474, 1.43 mg, 2.39 umol, 1% yield, 96.7% purity) was obtainedas a white solid. LCMS [ESI, M+1]: 580.

¹H NMR (400 MHz, chloroform-d) δ=8.22 (d, J=6.8 Hz, 1H), 7.90-7.82 (m,1H), 7.61 (d, J=8.4 Hz, 1H), 7.55-7.47 (m, 2H), 7.44 (t, J=7.6 Hz, 1H),7.15 (d, J=7.2 Hz, 1H), 5.26-4.89 (m, 1H), 4.60-4.34 (m, 4H), 4.33-4.16(m, 3H), 4.14-3.96 (m, 1H), 3.95-3.80 (m, 1H), 3.78-3.50 (m, 2H),3.50-3.28 (m, 2H), 3.27-3.07 (m, 3H), 3.06-2.82 (m, 3H), 2.80-2.64 (m,2H), 2.51 (d, J=12.4 Hz, 3H), 2.38-2.24 (m, 1H), 2.14-2.00 (m, 1H),1.97-1.85 (m, 2H).

Example 475

2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2,3,3-trideuterioprop-2-enoyl)piperazin-2-yl]acetonitrile

Step A:2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2,3,3-trideuterioprop-2-enoyl)piperazin-2-yl]acetonitrile.To a solution of deuterio 2,3,3-trideuterioprop-2-enoate (68.8 mg, 904umol, 3 eq) and DIEA (234 mg, 1.81 mmol, 315 uL, 6 eq) in MeCN (3 mL)was added MsCl (69.1 mg, 603 umol, 46.7 uL, 2 eq) at 5° C. for 0.5 hour.To the resulting reaction was added2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(150 mg, 301 umol, 1 eq). The reaction mixture was stirred at 5° C. for1 hour. Then the reaction mixture was heated to 80° C. for 12 hrs. Uponcompletion, the reaction mixture was quenched by water (0.5 mL). Theresidue mixture was purified by prep-HPLC (column: Phenomenex Gemini150*25 mm*10 um; mobile phase: [water (0.05% ammonia hydroxidev/v)-ACN]; B %: 50%-80%, 12 min) to give title compound2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2,3,3-trideuterioprop-2-enoyl)piperazin-2-yl]acetonitrile(EXAMPLE 475, 34.2 mg, 60.2 umol, 20% yield, 97.7% purity) as a whitesolid. LCMS [ESI, M+1]: 555.

¹H NMR (400 MHz, CHLOROFORM-d) δ=8.28-8.16 (m, 1H), 7.91-7.83 (m, 1H),7.63 (d, J=8.0 Hz, 1H), 7.56-7.48 (m, 2H), 7.45 (t, J=7.6 Hz, 1H), 7.16(d, J=7.2 Hz, 1H), 5.28-4.94 (m, 1H), 4.41 (dd, J=5.2, 10.8 Hz, 1H),4.36-4.24 (m, 2H), 4.23-4.11 (m, 2H), 4.04 (br d, J=11.6 Hz, 2H),3.73-3.25 (m, 3H), 3.22-2.74 (m, 7H), 2.69 (td, J=6.4, 13.2 Hz, 1H),2.50 (s, 3H), 2.36-2.24 (m, 1H), 2.15-2.02 (m, 1H), 1.83-1.77 (m, 3H).

Example 476

2-[(2S)-4-[7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-(3-fluoropyrrolidin-1-yl)but-2-enoyl]piperazin-2-yl]acetonitrile

Insert: (E)-4-bromobut-2-enoyl chloride. A solution of(E)-4-bromobut-2-enoic acid (1.0 g, 6.06 mmol, 1.0 eq) in (COCl)₂ (14.5g, 114 mmol, 10.0 mL, 18.9 eq) and DCM (10.0 mL) was stirred at 70° C.for 2 hours. After completion, the mixture was concentrated undervacuum. The product (E)-4-bromobut-2-enoyl chloride (1.0 g, crude) wasobtained as yellow oil. The crude compound was used directly to the nextstep without further purification.

Step A:2-[(2S)-4-[7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-2-(cyanomethyl)-4-[7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(Intermediate 73, 200 mg, 347 umol, 1.0 eq) in dioxane (2.0 mL) wasadded HCl·dioxane (4.0 M, 2.0 mL, 23.0 eq). The mixture was stirred at25° C. for 0.5 hour. After completion, the reaction mixture wasconcentrated under reduced pressure to give a residue. The residue wasadjusted pH=7 with saturated of NaHCO₃ aqueous solution and extractedwith EA (5.0 mL×3). The combined organic layers were washed with brine(10.0 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give the residue. The product2-[(2S)-4-[7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(160 mg, crude) was obtained as a yellow solid and used into the nextstep without further purification.

Step B:2-[(2S)-1-[(E)-4-bromobut-2-enoyl]-4-[7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(160 mg, 336 umol, 1.0 eq) in DCM (6.0 mL) was added Py (532 mg, 6.73mmol, 543 uL, 20.0 eq) and (E)-4-bromobut-2-enoyl chloride (246 mg, 1.35mmol, 4.0 eq) in DCM (2.0 mL). The mixture was stirred at 0° C. for 1hour. After completion, the reaction mixture was quenched by additionMeOH (5.0 mL) at 0° C., and then concentrated under reduced pressure togive a residue. The product2-[(2S)-1-[(E)-4-bromobut-2-enoyl]-4-[7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(200 mg, crude) was obtained as a yellow oil and used into the next stepwithout further purification. LCMS [ESI, M+1]: 622.

Step C:2-[(2S)-4-[7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-(3-fluoropyrrolidin-1-yl)but-2-enoyl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-1-[(E)-4-bromobut-2-enoyl]-4-[7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(200 mg, 321 umol, 1.0 eq) in DCM (3.0 mL) was added K₂CO₃ (88.8 mg, 642umol, 2.0 eq), KI (2.67 mg, 16.1 umol, 0.05 eq) and 3-fluoropyrrolidine(403 mg, 3.21 mmol, 10.0 eq, HCl salt). The mixture was stirred at 0° C.for 1 hour. After completion, the reaction mixture was concentratedunder reduced pressure to give a residue. The residue was adjusted pH=7with saturated of NaHCO₃ aqueous solution and extracted with EA (10.0mL×3). The combined organic layers were washed with brine (20.0 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive the residue. The residue was purified by prep-HPLC (column: Gemini150*25 5 u; mobile phase: [water (0.04% NH3H2O)-ACN]; B %: 60%-84%, 10min). The residue was concentrated under reduced pressure and thenlyophilization to give title compound2-[(2S)-4-[7-(2,3-dimethylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-(3-fluoropyrrolidin-1-yl)but-2-enoyl]piperazin-2-yl]acetonitrile(EXAMPLE 476, 123 mg, 193 umol, 56% yield in three steps, 99.2% purity)was obtained as a yellow solid. LCMS [ESI, M+1]: 631.

¹H NMR (400 MHz, Chloroform-d) δ 7.16-7.07 (m, 1H), 7.02-6.92 (m, 3H),6.59-6.41 (m, 1H), 5.31-5.10 (m, 1H), 5.09-4.46 (m, 1H), 4.38 (dd,J=4.8, 10.4 Hz, 1H), 4.26-3.83 (m, 6H), 3.80-3.45 (m, 1H), 3.42-3.24 (m,3H), 3.23-3.15 (m, 1H), 3.14-3.03 (m, 3H), 3.02-2.83 (m, 4H), 2.82-2.62(m, 4H), 2.54-2.49 (m, 1H), 2.47 (s, 3H), 2.32-2.26 (m, 6H), 2.25-2.17(m, 1H), 2.16-2.09 (m, 1H), 2.08-2.02 (m, 1H), 1.92-1.78 (m, 4H).

Example 477

2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2,3,3-trideuterioprop-2-enoyl)piperazin-2-yl]acetonitrile

Step A:2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2,3,3-trideuterioprop-2-enoyl)piperazin-2-yl]acetonitrile.To the solution of deuterio 2,3,3-trideuterioprop-2-enoate (56.6 mg, 744umol, 3 eq) and DIEA (481 mg, 3.72 mmol, 648 uL, 15 eq) in ACN (3 mL)was added MsCl (56.8 mg, 496 umol, 38.4 uL, 2 eq) at 5° C., the mixturewas stirred at 5° C. for 0.5 hour. Then to the mixture was added2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(Intermediate 71, 150 mg, 248 umol, 1 eq, 2 HCl), the resulting mixturewas stirred at 5° C. for 1 hour. Then the mixture was heated to 80° C.and stirred at 80° C. for 12 hours. The mixture was quenched by Water(0.5 mL). The reaction mixture was purified by prep-HPLC (column:Phenomenex Gemini 150*25 mm*10 um; mobile phase: [water (0.05% ammoniahydroxide v/v)-ACN]; B %: 50%-80%, 10 min) to give title compound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2,3,3-trideuterioprop-2-enoyl)piperazin-2-yl]acetonitrile(EXAMPLE 477, 13.0 mg, 21.6 umol, 9% yield. 98.2% purity) as a off-whitesolid. LCMS [ESI, M+1]: 589.

¹H NMR (400 MHz, chloroform-d) δ=7.76 (br d, J=8.4 Hz, 1H), 7.62 (t,J=7.6 Hz, 1H), 7.53 (d, J=7.2 Hz, 1H), 7.45 (td, J=8.0, 13.2 Hz, 1H),7.34 (t, J=7.6 Hz, 1H), 7.26-7.18 (m, 1H), 5.10 (br s, 1H), 4.49-4.33(m, 2H), 4.21-4.01 (m, 3H), 3.96-3.79 (m, 2H), 3.60 (br d, J=6.8 Hz,1H), 3.44 (br d, J=13.6 Hz, 1H), 3.32-2.97 (m, 5H), 2.88-2.53 (m, 4H),2.48 (d, J=2.8 Hz, 3H), 2.29 (br d, J=8.8 Hz, 1H), 2.11-2.00 (m, 1H),1.87-1.71 (m, 3H).

Example 478

2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile

2-fluoroprop-2-enoyl chloride. To a solution of 2-fluoroprop-2-enoicacid (400 mg, 4.44 mmol, 1 eq) in DCM (4 mL) was added (COCl)₂ (846 mg,6.66 mmol, 583 uL, 1.5 eq) and DMF (32.5 mg, 444 umol, 34.2 uL, 0.1 eq).The mixture was stirred at 25° C. for 2 hrs. The reaction mixture wasconcentrated under reduced pressure to remove a part of solvent and givea residue in DCM. Compound 2-fluoroprop-2-enoyl chloride (400 mg, crude)was obtained as a yellow liquid and used into the next step withoutfurther purification.

Step A:2-[(2S)-4-[7-(8-chloro-1-naphthyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(300 mg, 528 umol, 1 eq, HCl) in DCM (5 mL) was added DIEA (1.73 g, 13.4mmol, 2.33 mL, 25.4 eq) and 2-fluoroprop-2-enoyl chloride (286 mg, 2.64mmol, 5 eq) in DCM (5 mL). The mixture was stirred at 0° C. for 1 hour.The reaction mixture was concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (Al₂O₃,Dichloromethane/Methanol=10/1 to 10/1). The residue was purified byprep-HPLC (column: Gemini 150*25 5 u; mobile phase [water (0.05% ammoniahydroxide v/v)-ACN]; B %: 55%-85%, 12 min). The residue was purified byprep-HPLC (column: Phenomenex Synergi C18 150*30 mm*4 um; mobile phase:[water (0.225% FA)-ACN]; B %: 20%-50%, 10.5 min). The residue wasconcentrated under reduced pressure to remove ACN, and thenlyophilzation. Title compound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile(EXAMPLE 478, 24.1 mg, 36.7 umol, 7% yield, 99.1% purity, FA) wasobtained as a brown solid.

SFC condition: “AD-3S_3_5_40_3 ML Column: Chiralpak AD-3 100×4.6 mmI.D., 3 um Mobile phase: methanol (0.05% DEA) in CO₂ from 5% to 40% Flowrate: 3 mL/min Wavelength: 220 nm”.

¹H NMR (400 MHz, Acetic) δ=7.82 (d, J=8.0 Hz, 1H), 7.69 (d, J=8.0 Hz,1H), 7.56 (d, J=7.6 Hz, 1H), 7.49 (t, J=7.6 Hz, 1H), 7.41-7.30 (m, 2H),5.58-5.25 (m, 2H), 5.17-4.59 (m, 4H), 4.57-4.28 (m, 3H), 4.24-3.78 (m,4H), 3.67-3.13 (m, 7H), 3.08 (br d, J=2.4 Hz, 3H), 2.98 (br d, J=6.4 Hz,1H), 2.83-2.61 (m, 1H), 2.45-2.29 (m, 1H), 2.24-2.08 (m, 3H).

Example 479

2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-fluorobut-2-enoyl]piperazin-2-yl]acetonitrile

Step A: ethyl (E)-4-fluorobut-2-enoate. A mixture of ethyl(E)-4-bromobut-2-enoate (2.00 g, 10.4 mmol, 1.43 mL, 1.00 eq) and AgF(3.94 g, 31.1 mmol, 674 uL, 3.00 eq) in acetonitrile (20.0 mL) wasstirred at 25° C. for 12 hours. The mixture was filtered and washed withTHF (10.0 mL), then concentrated under vacuum to give ethyl(E)-4-fluorobut-2-enoate (2.50 g, crude) as a yellow oil and used intonext step without further purification.

¹H NMR (400 MHz, chloroform-d) δ=7.04-6.89 (m, 1H), 6.12 (qd, J=2.0,16.0 Hz, 1H), 5.14-4.94 (m, 2H), 4.22 (q, J=6.8 Hz, 2H), 1.30 (t, J=6.8Hz, 3H).

Step B: (E)-4-fluorobut-2-enoic acid. A mixture of ethyl(E)-4-fluorobut-2-enoate (0.10 g, crude) and NaOH (121 mg, 3.03 mmol) inTHF (1.00 mL) and H₂O (1.00 mL) was stirred at 25° C. for 2 hours. ThepH value was adjusted to 1-3 by HCl (1N, 5.00 mL), extracted with ethylacetate (3×10.0 mL), the organic layer was dried over Na₂SO₄, filteredand concentrated under vacuum to give (E)-4-fluorobut-2-enoic acid (0.02g, 192 mmol, two steps 46%) as a yellow oil and used into next stepwithout further purification.

¹H NMR (400 MHz, chloroform-d) δ=8.37-7.31 (m, 1H), 7.15-7.01 (m, 1H),6.15 (dd, J=1.6, 16.0 Hz, 1H), 5.22-4.96 (m, 2H).

Step C:2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-fluorobut-2-enoyl]piperazin-2-yl]acetonitrile.To a solution of (s)-4-fluorobut-2-enoic acid (7.32 mg, 70.4 umol, 2 eq)and Py (8.35 mg, 106 umol, 8.52 uL, 3.00 eq) in acetonitrile (1.00 mL)was added MsCl (8.06 mg, 70.4 umol, 5.45 uL, 2.00 eq) at 0° C. Afterstirred at 0° C. for 1 hour,2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(0.02 g, 35.2 umol, 1.00 eq, HCl) was added into the mixture. Themixture was stirred at 25° C. for 12 h. The mixture was diluted withwater (5.00 mL), extracted with ethyl acetate (3×5.00 mL), the organiclayer was dried over Na₂SO₄, filtered and concentrated under vacuum. Theresidue was purified by prep-HPLC (column: Gemini 150*25 5 u; mobilephase [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 50%-80%, 12 min).The desired fraction was collected and lyophilized to give titlecompound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-fluorobut-2-enoyl]piperazin-2-yl]acetonitrile(EXAMPLE 479, 3.01 mg, 4.82 umol, 14.0% yield, 98.9% purity) as a brownsolid. LCMS [ESI, M+1]: 618.

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.76 (br d, J=8.0 Hz, 1H), 7.62 (t,J=7.2 Hz, 1H), 7.53 (d, J=7.2 Hz, 1H), 7.45 (td, J=7.6, 12.8 Hz, 1H),7.34 (t, J=7.6 Hz, 1H), 7.26-7.17 (m, 1H), 7.09-6.91 (m, 1H), 6.59 (brd, J=15.6 Hz, 1H), 5.19-5.05 (m, 2H), 4.49-4.36 (m, 2H) 4.22-3.79 (m,5H), 3.76-2.96 (m, 81H), 2.92-2.55 (m, 4H), 2.48 (d, J=2.4 Hz, 3H), 2.29(br d, J=9.6 Hz, 1H), 2.06 (br d, J=10.0 Hz, 1H), 1.83-1.71 (m, 3H).

Example 480

2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-(3-fluoropyrrolidin-1-yl)but-2-enoyl]piperazin-2-yl]acetonitrile

Insert: (E)-4-bromobut-2-enoyl chloride. To a solution of(E)-4-bromobut-2-enoic acid (930 mg, 5.64 mmol, 1.0 eq) in DCM (2.0 mL)was added (COCl)₂ (2.90 g, 22.9 mmol, 2.0 mL, 4.05 eq). The mixture wasstirred at 60° C. for 12 hours. After completion, the mixture wasconcentrated under vacuum. The product (E)-4-bromobut-2-enoyl chloride(650 mg, crude) was obtained as yellow oil and used directly to the nextstep without further purification.

Step A:2-[(2S)-1-[((E)-4-bromobut-2-enoyl]-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(Intermediate 71, 150 mg, 282 umol, 1.0 eq) in DCM (3.0 mL) was added Py(446 mg, 5.64 mmol, 455 uL, 20.0 eq) and (E)-4-bromobut-2-enoyl chloride(207 mg, 1.13 mmol, 4.0 eq) in DCM (1.0 mL). The mixture was stirred at0° C. for 1 hour. After completion, the reaction mixture wasconcentrated under reduced pressure to give a residue. The product2-[(2S)-1-[((E)-4-bromobut-2-enoyl]-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(150 mg, crude) was obtained as brown oil and used into the next stepwithout further purification. LCMS [ESI, M+1]: 680.

Step B:2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-(3-fluoropyrrolidin-1-yl)but-2-enoyl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-1-[(E)-4-bromobut-2-enoyl]-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(150 mg, 221 umol, 1.0 eq) in DCM (10.0 mL) was added K₂CO₃ (366 mg,2.65 mmol, 12.0 eq), KI (1.83 mg, 11.0 umol, 0.05 eq) and3-fluoropyrrolidine (277 mg, 2.21 mmol, 10.0 eq, HCl). The mixture wasstirred at 0° C. for 0.5 hour. After completion, the reaction mixturewas concentrated under reduced pressure to give a residue. The residuewas adjusted pH˜7 with saturated NaHCO₃ aqueous solution and extractedwith EA (3×10 mL). The combined organic layers were washed with brine(20 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give the residue. The residue was purified by prep-HPLC(column: Gemini 150*25 5 u; mobile phase: [water (0.04% NH₃·H₂O)-ACN]; B%: 60%-84%, 10 min). The residue was concentrated under reduced pressureand then lyophilization. Title compound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-(3-fluoropyrrolidin-1-yl)but-2-enoyl]piperazin-2-yl]acetonitrile(EXAMPLE 480, 9.67 mg, 14.0 umol, 6% yield, 99.2% purity) was obtainedas yellow solid. LCMS [ESI, M+1]: 687.

¹H NMR (400 MHz, Chloroform-d) δ 7.76 (br d, J=8.0 Hz, 1H), 7.62 (t,J=7.8 Hz, 1H), 7.26 (br d, J=7.2 Hz, 1H), 7.49-7.40 (m, 1H), 7.34 (t,J=7.8 Hz, 1H), 7.27-7.17 (m, 1H), 7.05-6.92 (m, 1H), 6.57-6.42 (m, 1H),5.32-5.11 (m, 1H), 5.10-4.50 (m, 1H), 4.47-4.35 (m, 2H), 4.19-4.00 (m,2H), 3.95-3.75 (m, 2H), 3.65-3.55 (m, 1H), 3.47-3.28 (m, 3H), 3.24-3.05(m, 4H), 3.04-2.86 (m, 4H), 2.85-2.71 (m, 2H), 2.70-2.50 (m, 3H),2.47-2.45 (m, 3H), 2.32-2.15 (m, 2H), 2.14-2.02 (m, 2H), 1.87-1.67 (m,4H).

Example 481

2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-(3-fluoroazetidin-1-yl)but-2-enoyl]piperazin-2-yl]acetonitrile

Insert: (E)-4-bromobut-2-enoyl chloride. To a solution of(E)-4-bromobut-2-enoic acid (1 g, 6.06 mmol, 1.0 eq) in DCM (5.0 mL) wasadded oxalyl dichloride (7.25 g, 57.1 mmol. 5.0 mL, 9.4 eq). The mixturewas stirred at 60° C. for 12 hours. After completion, the reactionmixture was concentrated under reduced pressure to give(E)-4-bromobut-2-enoyl chloride (850 mg, crude) as yellow oil which wasused for the next step without further purification.

Step A: Intermediate 71.2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(310 mg, 414 umol, 1.0 eq) in dioxane (4.0 mL) was added HCl/dioxane(4.0 M, 4.0 mL, 39.0 eq) at 25° C. The mixture was stirred at 25° C. for0.5 hour. After completion, the reaction mixture was quenched bysaturated NaHCO₃ aqueous solution (20.0 mL), and then extracted with EA(3×40.0 mL). The combined organic layers were washed with saturated NaClaqueous solution (100.0 mL), dried over Na₂SO₄, filtered andconcentrated to give a residue2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(250 mg, crude) as yellow solid. The crude product was used into thenext step without further purification. LCMS [ESI, M+1]: 532.

Step B:2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-(3-fluoroazetidin-1-yl)but-2-enoyl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(Intermediate 71, 150 mg, 282 umol, 1.0 eq, crude) in DCM (6.0 mL) wasadded Py (446 mg, 5.6 mmol, 455 uL, 20.0 eq) and (E)-4-bromobut-2-enoylchloride (207 mg, 1.2 mmol, 4.0 eq. crude) in DCM (1.0 mL). The mixturewas stirred at 0° C. for 1 hour. Then K₂CO₃ (779 mg, 5.6 mmol, 20.0 eq),KI (4.6 mg, 28.2 umol, 0.1 eq) and 3-fluoroazetidine (472 mg, 4.2 mmol,15.0 eq, HCl) was added at 0° C. Then the mixture was stirred at 25° C.for 12 hours. After completion, the mixture was filtered andconcentrated under reduced pressure. The residue was purified byprep-HPLC (column: Phenomenex Gemini 150*25 mm*10 um; mobile phase:[water (10.0 mM NH₄HCO₃)-ACN]; B %: 55%-85%, 10 min.) and lyophilizationto give title compound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-(3-fluoroazetidin-1-yl)but-2-enoyl]piperazin-2-yl]acetonitrile(EXAMPLE 481, 10.8 mg, 15.7 umol, 6% yield, 98% purity) as yellow solid.LCMS [ESI, M+1]: 673.

SFC Conditions: 100%. e.e.

¹H NMR (400 MHz, Chloroform-d) δ 7.77 (d, J=8.0 Hz, 1H), 7.63 (t, J=7.8Hz, 1H), 7.54 (d, J==7.2 Hz, 1H), 7.50-7.43 (m, 1H), 7.35 (t, J==7.8 Hz,1H), 7.26-7.21 (m, 1H), 6.89 (d, J=15.2 Hz, 1H), 6.42 (d, J=14.8 Hz,1H), 5.26-4.62 (m, 1H), 5.11 (t, J=5.2 Hz, 1H), 4.80-4.37 (m, 2H),4.20-4.08 (m, 2H), 3.92 (br d, J=17.6 Hz, 1H), 3.86-3.71 (m, 3H), 3.60(s, 1H), 3.52-3.47 (m, 1H), 3.45-3.33 (m, 1H), 3.28-3.21 (m, 3H),3.16-3.11 (m, 3H), 3.03 (dd, J=8.4, 16.8 Hz, 1H), 2.82-2.60 (m, 4H),2.49 (d, J=2.8 Hz, 3H), 2.37-2.25 (m, 1H), 2.09-2.03 (m, 1H), 1.86-1.83(m, 1H), 1.78-1.76 (m, 3H).

Example 482

2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-[methyl(2,2,2-trifluoroethyl)amino]but-2-enoyl]piperazin-2-yl]acetonitrile

Insert: (E)-4-bromobut-2-enoyl chloride. A solution of(E)-4-bromobut-2-enoic acid (600 mg, 3.64 mmol, 1.0 eq) in (COCl)₂ (10.2g, 80.0 mmol, 7.0 mL, 22.0 eq) and DCM (7.0 mL) was stirred at 70° C.for 12 hours. After completion, the reaction mixture was concentrated togive (E)-4-bromobut-2-enoyl chloride (500 mg, crude) as yellow oil. Thecrude product was used for the next step without further purification.

Step A:2-[(2S)-1-[(E)-4-bromobut-2-enoyl]-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile (100 mg, 188 umol,1.0 eq) and pyridine (119 mg, 1.50 mmol, 121 uL, 8.0 eq) in DCM (2.0 mL)was added (E)-4-bromobut-2-enoyl chloride (138 mg, 752 umol, 4.0 eq).The mixture was stirred at 0° C. for 0.5 hour. After completion, thereaction mixture was concentrated to give2-[(2S)-1-[(E)-4-bromobut-2-enoyl]-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(130 mg, crude) as yellow oil. LCMS [ESI, M+1]: 678, 680.

Step B:2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-[methyl(2,2,2-trifluoroethyl)amino]but-2-enoyl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-1-[(E)-4-bromobut-2-enoyl]-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(128 mg, 189 umol, 1.0 eq), K₂CO₃ (130 mg, 943 umol, 5.0 eq) and KI(9.39 mg, 56.6 umol, 0.30 eq) in DCM (3.0 mL) was added2,2,2-trifluoro-N-methyl-ethanamine (213 mg, 1.88 mmol, 10.0 eq) inportions. The mixture was stirred at 0-25° C. for 12 hours. Aftercompletion, the mixture was concentrated under vacuum. The obtainedproduct was purified by prep-HPLC (column: Gemini 150*25 5 u; mobilephase: [water (0.04% NH₃·H₂O)-ACN]; B %: 70%-100%, 10 min) to give titlecompound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-[methyl(2,2,2-trifluoroethyl)amino]but-2-enoyl]piperazin-2-yl]acetonitrile(EXAMPLE 482, 2.87 mg, 3.84 umol, 2% yield, 95% purity) as white solid.LCMS [ESI, M+1]: 711.

¹H NMR (400 MHz, Chloroform-d) δ 7.76 (br d, J=7.6 Hz, 1H), 7.62 (t,J=7.6 Hz, 1H), 7.53 (d, J=7.2 Hz, 1H), 7.49-7.40 (m, 1H), 7.34 (t, J=7.8Hz, 1H), 7.27-7.18 (m, 1H), 6.95-6.79 (m, 1H), 6.54-6.38 (m, 1H),5.12-4.50 (m, 1H), 4.48-4.35 (m, 2H), 4.24-3.99 (m, 3H), 3.96-3.78 (m,2H), 3.77-3.64 (m, 1H), 3.61-3.53 (m, 1H), 3.52-3.34 (m, 3H), 3.33-2.97(m, 7H), 2.92-2.76 (m, 1H), 2.75-2.65 (m, 1H), 2.63-2.55 (m, 1H), 2.51(s, 3H), 2.49 (br d, J=3.2 Hz, 3H), 2.35-2.25 (m, 1H), 2.13-1.99 (m,1H), 1.89-1.67 (m, 3H).

Example 483

2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(4-hydroxybut-2-ynoyl)piperazin-2-yl]acetonitrile

Step A:2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(4-hydroxybut-2-ynoyl)piperazin-2-yl]acetonitrile.To a solution of 4-[tert-butyl(dimethyl)silyl]oxybut-2-ynoic acid (129mg, 564 umol, 1.50 eq) and DIEA (194 mg, 1.50 mmol, 262 uL, 4.00 eq) inDMF (2.00 mL) was added HATU (214 mg, 564 umol, 1.50 eq) at 0° C. Afterstirred at 0° C. for 10 mins,2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(0.20 g, 376 umol, 1.00 eq) was added into the mixture. After stirred at25° C. for 12 hours, the mixture was diluted with ethyl acetate (10.0mL), washed with brine (3×10.0 mL), dried over Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by reversed phaseflash [water (FA, 0.10%)/acetonitrile]. The desired fractions werecollected, neutralized with saturated sodium bicarbonate (5.00 mL) topH>7 and extracted with ethyl acetate (3×20.0 mL). The organic layerswere washed with brine (1×30.0 mL), dried over Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by prep-HPLC column:Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225%,FA)-ACN]; B %: 10%-40%, 10 min. The desired fractions were collected andlyophilized to give title compound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(4-hydroxybut-2-ynoyl)piperazin-2-yl]acetonitrile(EXAMPLE 483, 10.1 mg, 15.3 umol, 4.1% yield, 99.6% purity, FA) as ayellow solid. LCMS [ESI, M+1]: 614.

¹H NMR (400 MHz, Acetic acid-d4) δ=7.82 (d, J=8.4 Hz, 1H), 7.69 (d,J=8.4 Hz, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.49 (t, J=7.6 Hz, 1H), 7.42-7.31(m, 2H), 5.14-4.73 (m, 4H), 4.70-4.23 (m, 5H), 4.01-3.81 (m, 3H),3.80-3.51 (m, 3H), 3.49-3.17 (m, 4H), 3.09 (m, 5H), 2.81-2.63 (m, 1H),2.45-2.34 (m, 1H), 2.22-2.08 (m, 3H).

Example 484

2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4,4-difluorobut-2-enoyl]piperazin-2-yl]acetonitrile

Step 1: 4,4-difluoro-3-hydroxy-butanoate. To a solution of ethyl4,4-difluoro-3-oxo-butanoate (5.00 g, 30.1 mmol, 1.00 eq) in toluene(150 mL) was added NaBH₄ (1.20 g, 31.7 mmol, 1.05 eq) at 0° C. Afterstirred at 25° C. for 4 hours, the mixture was diluted with water (50.0mL) at 0° C. and extracted with ethyl acetate (3×100 mL). The extractswere washed with brine (1×100 mL), dried over Na₂SO₄, filtered andconcentrated under vacuum to give ethyl 4,4-difluoro-3-hydroxy-butanoate(4.30 g, crude) as a yellow oil and used into next step without furtherpurification.

¹H NMR (400 MHz, DMSO-d6) δ=6.05-5.87 (m, 1H), 5.86-5.72 (m, 1H),4.11-4.01 (m, 2H), 2.57 (dd, J=4.0, 15.6 Hz, 1H), 2.38 (dd, J=9.2, 15.6Hz, 1H), 1.21-1.17 (m, 3H).

Step 2: ethyl (E)-4,4-difluorobut-2-enoate. To a solution of ethyl4,4-difluoro-3-hydroxy-butanoate (3.00 g, crude) in dichloromethane(20.0 mL) was added TEA (1.81 g, 17.8 mmol, 2.48 mL) and MsCl (3.68 g,32.1 mmol, 2.49 mL) at 0° C. After stirred for 4 hours, to the mixturewas added TEA (3.61 g, 35.68 mmol, 4.97 mL, 2 eq) 0° C. After warmed upto 25° C. and stirred for 12 hours, the mixture was diluted with water(10.0 mL), washed with HCl (1N, 1×20.0 mL) and brine (1×20.0 mL), driedover Na₂SO₄, filtered and concentrated under vacuum to give ethyl(E)-4,4-difluorobut-2-enoate (1.40 g, 9.33 mmol, two steps 44% yield) asa colourless oil and used into next step with further purification.

¹H NMR (400 MHz, chloroform-d) δ=6.81 (m, 1H), 6.29 (dt, J=2.8, 1.6 Hz,1H), 6.23 (dd, J=4.0, 55.2 Hz, 1H), 4.25 (q, J=7.2 Hz, 2H), 1.31 (t,J=7.2 Hz, 3H).

Step 3: (E)-4,4-difluorobut-2-enoic acid. A mixture of ethyl(E)-4,4-difluorobut-2-enoate (1.30 g, 8.66 mmol, 1.00 eq) and NaOH (1.39g, 34.6 mmol, 4.00 eq) in THF (5.00 mL) and H₂O (5.00 mL) was stirred at25° C. for 2 hours. The mixture was acidified with HCl (2N, 20.0 mL) topH=1˜3 and extracted with ethyl acetate (3×20.0 mL). The organic layerswere dried over Na₂SO₄, filtered and concentrated under vacuum to give(E)-4,4-difluorobut-2-enoic acid (0.35 g, 2.87 mmol, 33% yield) as ayellow solid and used into next step without further purification.

¹H NMR (400 MHz, chloroform-d) δ=6.92 (m, 1H), 6.32 (dtd, J=0.8, 2.8,16.8 Hz, 1H), 6.27 (dtd, J=1.2, 54.8 Hz, 4.0, 1H).

Step A:2-[(2s)-4-[7-(8-chloro-1-naphthyl)-2-[[(2s)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5_(H)-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4,4-difluorobut-2-enoyl]piperazin-2-yl]acetonitrile.A mixture of (E)-4,4-difluorobut-2-enoic acid (68.8 mg, 564 umol, 1.50eq), EDCI (108 mg, 564 umol, 1.50 eq) and HOBt (50.8 mg, 376 umol, 1.00eq) in Py (3 mL) was stirred at 0° C. for 15 min, then2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(Intermediate 71, 0.20 g, 376 umol, 1.00 eq) was added into the mixture.After stirred at 0° C. for 1 hour and 25° C. for 1 hour, the mixture wasdiluted with water (10.0 mL), extracted with ethyl acetate (1×10.0 mL).The extracts were washed with brine (1×10.0 mL), dried over Na₂SO₄,filtered and concentrated under vacuum. The residue was purified byreversed phase flash [water (FA, 0.10%)/acetonitrile]. The desiredfractions were collected and the mixture was neutralized with saturatedsodium bicarbonate (5.00 mL), extracted with ethyl acetate (3×20.0 mL).The organic layers were washed with brine (1×30.0 mL), dried overNa₂SO₄, filtered and concentrated under vacuum. The residue was purifiedby prep-HPLC (column: Gemini 150*25 5 u, mobile phase: [water (0.05%ammonia hydroxide v/v)-ACN]; B %: 55%-85%, 12 min). The desiredfractions were collected and lyophilized to give title compound2-[(2s)-4-[7-(8-chloro-1-naphthyl)-2-[[(2s)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5_(H)-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4,4-difluorobut-2-enoyl]piperazin-2-yl]acetonitrile(EXAMPLE 484, 66.9 mg, 104 umol, 28% a yield, 98.7% purity) as a yellowsolid. LCMS [ESI, M+1]: 636.

¹H NMR (400 MHz, chloroform-d) δ=7.76 (d, J=8.0 Hz, 1H), 7.62 (t, J=7.2Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 7.45 (td, J=7.6, 12.8 Hz, 1H),7.37-7.31 (m, 1H), 7.27-7.18 (m, 1H), 6.88-6.71 (m, 2H), 6.45-6.12 (m,1H), 5.17-4.59 (m, 1H), 4.55-4.41 (m, 1H), 4.40-4.33 (m, 1H), 4.21-3.69(m, 5H), 3.64-3.32 (m, 2H), 3.31-2.97 (m, 51H), 2.96-2.52 (m, 41H), 2.47(d, J=1.6 Hz, 3H), 2.33-2.23 (m, 1H), 2.11-2.00 (m, 1H), 1.90-1.77 (m,3H).

Example 485

2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[2-(methoxymethyl)prop-2-enoyl]piperazin-2-yl]acetonitrile

Step 1: 1-(2-(ethoxycarbonyl)allyl)-1,4-diazabicyclo[2.2.2]octan-1-iumbromide. To ethyl 2-(bromomethyl)prop-2-enoate (15 g, 77.7 mmol, 1 eq)in THF (5 mL) was added DABCO (10.5 g, 93.6 mmol, 10.3 mL, 1.20 eq) andthe resulting mixture was stirred at 25° C. for 2 hours. The precipitatewas formed and filtered under nitrogen atmosphere. The filter cake wascollected to give1-(2-(ethoxycarbonyl)allyl)-1,4-diazabicyclo[2.2.2]octan-1-ium bromide(15 g, 49.6 mmol, 64% yield) as a light yellow solid which was useddirectly in the next step without further purification.

Step 2: ethyl 2-(methoxymethyl)prop-2-enoate. A mixture of1-(2-(ethoxycarbonyl)allyl)-1,4-diazabicyclo[2.2.2] octan-1-ium bromide(15 g, 49.6 mmol, 1 eq) and TEA (10.5 g, 104 mmol, 14.5 mL, 2.09 eq) inMeOH (150 mL) was stirred at 25° C. for 16 hours. The solvent wasevaporated under vacuum (25° C.). The residue was dissolved into DCM (40ml) and then washed with 5% aqueous citric acid solution (1×40 mL) andsaturated sodium bicarbonate aqueous solution (1×40 mL). The organiclayer was dried over sodium sulfate, filtered and concentrated undervacuum at 25° C. to give ethyl 2-(methoxymethyl)prop-2-enoate (5.3 g,36.8 mmol, 74% yield) as a yellow liquid which was used directly in thenext step without further purification.

Step 3: 2-(methoxymethyl)prop-2-enoic acid. To a solution of ethyl2-(methoxymethyl)prop-2-enoate (5.1 g, 35.4 mmol, 1 eq) in THF (71 mL)was added a solution of NaOH (5.66 g, 142 mmol, 4 eq) in H₂O (71 mL) at5° C. The mixture was stirred at 25° C. for 2 hours. Upon completion,the THF was evaporated under vacuum. The pH of the mixture was adjustedto 3 with 1 M HCl and extracted with EtOAc (3×70 mL). The organic layerswere dried over Na₂SO₄ and concentrated under vacuum to give2-(methoxymethyl)prop-2-enoic acid (3.4 g, 26.4 mmol, 75% yield, 90%purity) as a light yellow liquid which was used directly in the nextstep without further purification.

¹H NMR (400 MHz, chloroform-d) δ=6.45 (d, J=1.2 Hz, 1H), 5.98 (q, J=1.6Hz, 1H), 4.16 (t, J=1.2 Hz, 2H), 3.42 (s, 3H).

Step A:2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[2-(methoxymethyl)prop-2-enoyl]piperazin-2-yl]acetonitrile.To a solution of 2-(methoxymethyl)prop-2-enoic acid (175 mg, 1.50 mmol,2 eq) and DIEA (389 mg, 3.01 mmol, 524 uL, 4 eq) in DCM (8 mL) was addedHATU (429 mg, 1.13 mmol, 1.5 eq) at −40° C. After stirred at −40° C. for10 minutes,2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(Intermediate 71, 400 mg, 752 umol, 1 eq) was added into the mixture.The mixture was stirred at −40° C. for 20 minutes, 0° C. for 0.5 hourand 25° C. for 1 hour. Upon completion, to the mixture was added water(10 mL) and extracted with DCM (2×20 mL). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated under vacuum. Theresidue was purified by chromatography (Al₂O₃, EtOAc/MeOH 100/1 to 40/1)and purified by prep-HPLC (column: Gemini 150*25 5 u; mobile phase:[water (0.05% ammonia hydroxide v/v)-ACN]; B %: 50%-80%, 12 min). Thedesired fractions were collected and lyophilized to give title compound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[2-(methoxymethyl)prop-2-enoyl]piperazin-2-yl]acetonitrile(EXAMPLE 485, 73.0 mg, 116 umol, 15% yield, 98.9% purity) as a off-whitesolid. LCMS [ESI, M+1]: 630.

SFC condition: Column: Chiralpak AS-3 100×4.6 mm I.D., 3 um Mobilephase: methanol (0.05% DEA) in CO₂ from 5% to 40% Flow rate: 3 mL/minWavelength: 220 nm.

¹H NMR (400 MHz, chloroform-d) δ=7.76 (br d, J=8 Hz, 1H), 7.62 (t, J=7.6Hz, 1H), 7.52 (d, J=7.61 Hz, 1H), 7.45 (td, J=7.6, 13.2 Hz, 1H),7.37-7.30 (m, 1H), 7.26-7.17 (m, 1H), 5.51 (s, 1H), 5.32 (br s, 1H),5.19-4.58 (m, 1H), 4.48-4.34 (m, 2H), 4.23-4.07 (m, 4H), 4.06-3.78 (m,3H), 3.64-3.55 (m, 1H), 3.39 (s, 3H), 3.36-2.72 (m, 8H), 2.71-2.53 (m,2H), 2.47 (s, 3H), 2.35-2.22 (m, 1H), 2.14-1.98 (m, 1H), 1.90-1.73 (m,3H).

Example 486

2-((S)-4-(7-(2,3-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4,4,4-trifluorobut-2-enoyl)piperazin-2-yl)acetonitrile

Step A: 2-tert-butyl4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate.In a round bottom flask, a solution of tert-butyl(S)-4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(5 g, 9.487 mmol) in dioxane (94.87 ml, 9.487 mmol) was sparged withargon and (S)-(1-methylpyrrolidin-2-yl)methanol (3.278 g, 28.46 mmol),Cs₂CO₃ (9.273 g, 28.46 mmol),Methanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II)(0.8078 g, 0.9487 mmol) were sequentially added under Argon and spargedfor an additional 5 minutes. The reaction mixture was capped and heatedat 100° C. overnight. The reaction was filtered through GF/F paper andconcentrated in vacuo. The concentrate was purified on the Combi Flash(0-12% MeOH in DCM with 2% NH₄OH) to provide tert-butyl4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(5.425 g, 8.508 mmol, 89.68% yield). ESI+APCI MS m/z 606.4 [M+H]⁺.

Step B: benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:tert-butyl4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(5.4 g, 8.915 mmol) was dissolved in dichloromethane (80.15 ml, 8.915mmol) and treated with Hydrochloric Acid (4.0M solution in1,4-dioxane)(11.14 ml, 44.57 mmol). The reaction stirred at roomtemperature for 1 hour. The reaction was diluted with more DCM and 1MNaOH and the layers separated. The organics were next washed with brine,dried over Na₂SO₄ and concentrated in vacuo to give benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(4.364 g, 8.631 mmol, 96.82% yield). ESI+APCI MS m/z 506.3 [M+H]⁺.

Step C:2-(S)-4-(7-(2,3-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:In a round bottom flask, a solution of benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(4.364 g, 8.631 mmol) in dioxane (43.15 ml, 8.631 mmol) was sparged withArgon for 5 minutes. 1-Bromo-2,3-dimethylbenzene (5.851 ml, 43.15 mmol),Cs₂CO₃ (14.06 g, 43.15 mmol), andMethanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II)(0.7348 g, 0.8631 mmol) were sequentially added under Argon and spargedfor an additional 5 min. The reaction mixture was capped and heated at100° C. ON. The reaction was cooled to room temperature. Ethyl acetatewas added and the reaction filtered through GF/F paper and concentratedin vacuo. The concentrate was purified twice via normal phasechromatography on the CombiFlash using 0-15% MeOH in DCM with 2% NH₄OHas eluent. Fractions containing desired product were collected andconcentrated in vacuo to give2-((S)-4-(7-(2,3-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(0.411 g, 0.8641 mmol, 100.1% yield). ESI+APCI MS m/z 476.3 [M+H]⁺.

Step D:2-((S)-4-(7-(2,3-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4,4,4-trifluorobut-2-enoyl)piperazin-2-yl)acetonitrile:To a solution of2-((S)-4-(7-(2,3-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(200 mg, 0.420 mmol), 4,4,4-Trifluorocrotonic Acid (118 mg, 0.841 mmol),DIEA (367 μl, 2.10 mmol) in DCM (4205 μl, 0.420 mmol) was added HATU(240 mg, 0.631 mmol) and the resulting mixture was stirred at roomtemperature for 5 hours. The reaction mixture was washed with Brine andthe aqueous layer extracted with DCM (2×). The combined organic layerswere dried over Na₂SO₄, concentrated, diluted in 60:40 ACN:H₂O andpurified on the Gilson (reverse prep HPLC), eluting with 5->95% ACN/0.1%TFA in water/0.1% TFA. Fractions containing product were combined andfree based with saturated bicarb and the organics extracted with DCM.The organics were dried over Na₂SO₄ and concentrated in vacuo to givetitle compound2-((S)-4-(7-(2,3-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4,4,4-trifluorobut-2-enoyl)piperazin-2-yl)acetonitrile(EXAMPLE 486, 28 mg, 0.0468 mmol, 11.1% yield). ESI+APCI MS m/z 598.3[M+H]⁺.

Example 487

2-((S)-4-(7-(2,3-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-(trifluoromethyl)acryloyl)piperazin-2-yl)acetonitrile

2-((S)-4-(7-(2,3-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-(trifluoromethyl)acryoyl)piperazin-2-yl)acetonitrile:The title compound was prepared following Example 486 substituting2-(Trifluoromethyl)propenoic acid for 4,4,4-Trifluorocrotonic Acid inStep D. ESI+APCI MS m/z 598.3 [M+H]⁺.

Example 488

2-((S)-4-(7-(2,3-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-(hydroxymethyl)acryloyl)piperazin-2-yl)acetonitrile

2-((S)-4-(7-(2,3-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-(hydroxymethyl)acryloyl)piperazin-2-yl)acetonitrile:The title compound was prepared following Example 486 substituting2-(hydroxymethyl)prop-2-enoic acid for 4,4,4-Trifluorocrotonic Acid inStep D. ESI+APCI MS m/z 560.3 [M+H]⁺.

Example 489

2-((S)-4-(7-(2,3-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4-methoxybut-2-enoyl)piperazin-2-yl)acetonitrile

Step A:2-((S)-4-(7-(2,3-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4-methoxybut-2-enoyl)piperazin-2-yl)acetonitrile:To a solution of2-((S)-4-(7-(2,3-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(50 mg, 0.1051 mmol) in DCM (1 mL) was added (E)-4-methoxybut-2-enoicacid (24.41 mg, 0.2102 mmol), N-ethyl-N-isopropylpropan-2-amine (0.03662ml, 0.2102 mmol) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium PF₆ (59.96 mg,0.1577 mmol) and the reaction mixture stirred at room temperature for 4hours. Water (1 mL) was next added and the reaction mixture stirred for5 minutes. The mixture was divided between EtOAc (10 mL) and 0.5M NaHCO₃(5 mL) and the layers separated. The organics were washed with brine (3mL), dried over Na₂SO₄ and evaporated in vacuo. The residue waschromatographed on silica gel using 3% MeOH+0.3% NH₄OH to 4% MeOH+0.4%NH₄OH as eluent to give title compound (EXAMPLE 489, 26 mg, 43%).ESI+APCI MS m/z 574.4 [M+H]⁺.

Example 490

2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4,4,4-trifluorobut-2-enoyl)piperazin-2-yl)acetonitrile

Step A: benzyl(S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:To a solution of benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4yl)piperazine-1-carboxylate (0.6 g, 1.2 mmol) in dioxanes (10 mL) wasadded 1-bromo-8-chloronaphthalene (0.37 g, 1.5 mmol) and the reactiondegassed with Ar for 15 minutes followed by addition of Cs₂CO₃ (1.2 g,3.6 mmol), Pd₂(dba)₃ (0.22 g, 0.24 mmol) and2-Dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (0.11 g, 0.24mmol) and the reaction heated to 100° C. for overnight. The reaction wasnext filtered through GFF paper and the filtrated concentrated in vacuo.The residue was next chromatographed using 1→10% (MeOH+2% NH₄OH)/DCM togive benzyl(S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(0.20 g, 0.30 mmol, 25% yield). ESI+APCI MS m/z 666.2 [M+H]⁺.

Step B:2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:A solution of benzyl(S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(0.17 g, 0.255 mmol) in THF (30 mL) was purged with N₂ followed byaddition of Pd/C (0.0272 g, 0.255 mmol). The reaction was evacuated byvacuum and backfilled with H₂ 3× and the mixture was stirred for 3 daysat room temperature. The reaction was again purged with N₂ followed byfiltering through celite and the filtrate concentrated in vacuo. Thematerial used crude in the next reaction. ESI+APCI MS m/z 532.2 [M+H]⁺.

Step C:2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4,4,4-trifluorobut-2-enoyl)piperazin-2-yl)acetonitrile:To a solution of2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(0.055 g, 0.10 mmol) in DCM (20 mL) was addedN-ethyl-N-isopropylpropan-2-amine (0.040 g, 0.31 mmol),(E)-4,4,4-trifluorobut-2-enoic acid (0.017 g, 0.12 mmol) and1-Propanephosphonic acid cyclic anhydride (0.033 g, 0.10 mmol) and thereaction stirred at room temperature for 30 minutes. Next additionalTEP3 and acid (0.24 mmol) were added and and the reaction an addition 1hour. The organics were next washed with 1 N NaOH, brine, dried overMgSO₄ and concentrated in vacuo. The material was chromatographed 2× onnormal phase silica (1→10% (MeOH+2% NH₄OH)/DCM) followed by purificationby gilson reverse prep HPLC using 5→95% ACN/water with 0.1% TFA asadditive. The PURE fractions were poured into basic water and extractedinto EtOAc. The organics were washed with brine, dried over MgSO₄ andconcentrated in vacuo to give title compound2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4,4,4-trifluorobut-2-enoyl)piperazin-2-yl)acetonitrile(EXAMPLE 490, 0.0094 g, 0.014 mmol, 14% yield). ESI+APCI MS m/z 654.2[M+H]⁺.

Example 491

2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4,4,4-trifluorobut-2-enoyl)piperazin-2-yl)acetonitrile

Step A:2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4,4,4-trifluorobut-2-enoyl)piperazin-2-yl)acetonitrile:At 0° C., to a 25 mL RBF containing N,N-dimethylformamide (2932 μl,0.293 mmol) was added2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(150 mg, 0.293 mmol) and Hunig's base (102 μl, 0.586 mmol). The reactionmixture was vigorously stirred while (E)-4,4,4-trifluorobut-2-enoic acid(49.3 mg, 0.352 mmol) was added in one portion. Next,1-Propanephosphonic acid cyclic anhydride (262 μl, 0.440 mmol) was addedslowly to the stirring mixture. The reaction was stirred for 2 hours at0° C. The reaction was treated with basic water and the aqueous layerextracted with EtOAc (3×). The combined organics were concentrated invacuo and resuspended in a 60:40 mixture of ACN:H₂O and purified on theGilson (reverse prep HPLC), eluting with 5->95% ACN/0.1% TFA inwater/0.1% TFA. Fractions containing product were combined andpartitioned between saturated bicarb and DCM. The aqueous layer wasextracted with DCM two more times. The organic layers were combined,dried over Na₂SO₄ and concentrated in vacuo to give title compound2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4,4,4-trifluorobut-2-enoyl)piperazin-2-yl)acetonitrile(EXAMPLE 491, 74.5 mg, 0.118 mmol, 40.1% yield). ESI+APCI MS m/z 634.3[M+H]⁺.

Example 492

2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-(trifluoromethyl)acryloyl)piperazin-2-yl)acetonitrile

2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-(trifluoromethyl)acryloyl)piperazin-2-yl)acetonitrile:The title compound was prepared following Example 491 substituting2-(trifluoromethyl)acrylic acid for (E)-4,4,4-trifluorobut-2-enoic acidin Step A. ESI+APCI MS m/z 634.2 [M+H]⁺.

Example 493

2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile

2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile:The title compound was prepared following Example 491 substituting3-(Pyridin-2-yl)acrylic acid for (E)-4,4,4-trifluorobut-2-enoic acid inStep A. ESI+APCI MS m/z 643.3 [M+H]⁺.

Example 494

2-((S)-1-((E)-3-(1-methyl-1H-pyrazol-4-yl)acryloyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-((S)-1-((E)-3-(1-methyl-1H-pyrazol-4-yl)acryloyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:The title compound was prepared following Example 491 substituting(2E)-3-(1-Methyl-1H-pyrazol-4-yl)acrylic acid for(E)-4,4,4-trifluorobut-2-enoic acid in Step A. ESI+APCI MS m/z 646.4[M+H]⁺.

Example 495

2-((S)-1-(E)-4,4-difluorobut-2-enoyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-((S)-1-(E)-4,4-difluorobut-2-enoyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:The title compound was prepared following Example 491 substituting4,4-Difluorobut-2-enoic acid for (E)-4,4,4-trifluorobut-2-enoic acid inStep A. ESI+APCI MS m/z 616.3 [M+H]⁺.

Example 496

2-((S)-4-(2-(((S)-1-methylpiperidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-3-(pyridin-3-yl)acryloyl)piperazin-2-yl)acetonitrile

Step A: To a solution of2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(0.12 g, 0.23 mmol) in DCM (10 mL) N-ethyl-N-isopropylpropan-2-amine(0.13 ml, 0.70 mmol), (E)-3-(pyridin-3-yl)acrylic acid (0.070 g, 0.47mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane2,4,6-trioxide (0.30 g, 0.47 mmol) and the reaction stirred at roomtemperature for 3 hours. The reaction was next poured into 1N NaOH andthe layers separated. The organics were next washed with brine, driedover MgSO4 and concentrated in vacuo. The material was next purified byGilson reverse prep HPLC eluting with 5→95 ACN/water with 0.1% TFA asmodifier. Fractions containing product were poured into 1N NaOH and theaqueous layer extracted with EtOAc (3×). The combined organics werewashed with brine, dried over MgSO₄ and concentrated in vacuo to givetitle compound2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-3-(pyridin-3-yl)acryloyl)piperazin-2-yl)acetonitrile(EXAMPLE 496, 0.040 g, 0.062 mmol, 27% yield). ESI+APCI MS m/z 643.3[M+H]⁺.

Example 497

2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(3-oxocyclopent-1-ene-1-carbonyl)piperazin-2-yl)acetonitrile

Step A:2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(3-oxocyclopent-1-ene-1-carbonyl)piperazin-2-yl)acetonitrile:2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(30 mg, 0.05863 mmol) and 3-oxocyclopent-1-enecarboxylic acid (9.612 mg,0.07622 mmol) were diluted with DMF (400 uL) followed by the addition ofDIEA (20.48 μl, 0.1173 mmol) and 1-propanephosphonic acid cyclicanhydride (52.35 μl, 0.08795 mmol). After stirring for 12 hours, thereaction was diluted with ethyl acetate and saturated sodiumbicarbonate. The layers were separated and the ethyl acetate was driedover MgSO4, filtered and concentrated. The material was purified onsilica gel eluting with 10% methanol/DCM (1% NH4OH) to afford titlecompound2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(3-oxocyclopent-1-ene-1-carbonyl)piperazin-2-yl)acetonitrile(EXAMPLE 497, 2.3 mg, 0.003711 mmol, 6.329% yield). ESI+APCI MS m/z620.3 [M+H]⁺.

Example 498

2-((S)-1-((E)-4-chlorobut-2-enoyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A:2-((S)-1-((E)-4-chlorobut-2-enoyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(30 mg, 0.05863 mmol) and gamma-chlorocrotonic acid (10.60 mg, 0.08795mmol) were diluted with DMF (400 uL) followed by the addition of DIEA(20.48 μl, 0.1173 mmol) and 1-propanephosphonic acid cyclic anhydride(55.84 μl, 0.09381 mmol). After stirring for 12 hours, the reaction wasdiluted with ethyl acetate and saturated sodium bicarbonate. The layerswere separated and the ethyl acetate was dried over MgSO4, filtered andconcentrated. The material was purified on silica gel eluting with 10%methanol/DCM (1% NH₄OH) to afford title compound2-((S)-1-((E)-4-chlorobut-2-enoyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(EXAMPLE 498, 4.5 mg, 0.007327 mmol, 12.50% yield). ESI+APCI MS m/z614.3 [M+H]⁺.

Example 499

(E)-4-((S)-2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-N,N-dimethyl-4-oxobut-2-enamide

Step A: Ethyl (E)-4-(dimethylamino)-4-oxobut-2-enoate: Fumaric acidmonoethyl ester (442 mg, 3.07 mmol) was diluted with DCM (5 mL) followedby the addition of oxalyl chloride (1533 μl, 3.07 mmol) and 1 drop ofDMF. After stirring for 15 minutes, dimethylamine (4600 μl, 9.20 mmol)was added and the reaction was stirred for 3 hours. The reaction wasdiluted with ethyl acetate and water. The layers were separated and theethyl acetate was dried over MgSO4, filtered and concentrated. Thematerial was purified on silica gel eluting with 10-70% ethylacetate/hexanes to afford ethyl (E)-4-(dimethylamino)-4-oxobut-2-enoate(382 mg, 2.23 mmol, 72.8% yield). ESI+APCI MS m/z 172.1 [M+H]⁺.

Step B: (E)-4-(dimethylamino)-4-oxobut-2-enoic acid: Ethyl(E)-4-(dimethylamino)-4-oxobut-2-enoate (382 mg, 2.23 mmol) was dilutedwith methanol (8 mL) followed by the addition of NaOH (4463 μl, 8.93mmol). After stirring for 4 hours, the reaction was diluted with 2N HCl(4.5 mL) and extracted with ethyl acetate. The ethyl acetate was driedover MgSO4, filtered and concentrated to afford(E)-4-(dimethylamino)-4-oxobut-2-enoic acid.

Step C:(E)-4-((S)-2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-N,N-dimethyl-4-oxobut-2-enamide:2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(30 mg, 0.05863 mmol) was diluted with DMF followed by the addition of(E)-4-(dimethylamino)-4-oxobut-2-enoic acid (10.07 mg, 0.07036 mmol),DIEA (20.48 μl, 0.1173 mmol) and 1-propanephosphonic acid cyclicanhydride (52.35 μl, 0.08795 mmol). After stirring for 12 hours, thereaction was diluted with ethyl acetate and saturated sodiumbicarbonate. The layers were separated and the ethyl acetate was driedover MgSO4, filtered and concentrated. The material was purified onsilica gel eluting with 10% methanol/DCM (1% NH4OH) to afford titlecompound(E)-4-((S)-2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-N,N-dimethyl-4-oxobut-2-enamide(EXAMPLE 499, 3.7 mg, 0.005810 mmol, 9.910% yield). ESI+APCI MS m/z637.3 [M+H]⁺.

Example 500

(E)-4-((S)-2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-4-oxobut-2-enamide

Step A: Ethyl (E)-3-cyanoacrylate: Ethyl cis-(beta-cyano)acrylate (1.0g, 7.99 mmol) was diluted with ACN (30 mL), placed under nitrogen andheated to reflux for 3 days. The reaction was allowed to cool and thenconcentrated. The material was purified on silica gel eluting withhexanes to afford ethyl (E)-3-cyanoacrylate (300 mg, 2.40 mmol, 30.0%yield).

Step B: (E)-4-amino-4-oxobut-2-enoic acid: Ethyl (E)-3-cyanoacrylate(300 mg, 2.40 mmol) was diluted with HCl (3996 μl, 24.0 mmol). Thereaction was placed under nitrogen and heated to 100° C. for 4 hours.The reaction was allowed to cool and then concentrated to afford(E)-4-amino-4-oxobut-2-enoic acid (214 mg, 1.86 mmol, 77.6% yield).

Step C:(E)-4-((S)-2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-4-oxobut-2-enamide:2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(20 mg, 0.039 mmol), HATU (30 mg, 0.078 mmol) and(E)-4-amino-4-oxobut-2-enoic acid (9.0 mg, 0.078 mmol) were diluted withDMF (400 uL) followed by the addition of DIEA (14 μl, 0.078 mmol). Afterstirring for 12 hours, the reaction was diluted with ethyl acetate andsaturated sodium bicarbonate. The layers were separated and the ethylacetate was dried over MgSO4, filtered and concentrated. The materialwas purified on silica gel eluting with 10% methanol/DCM (1% NH4OH) toafford title compound(E)-4-((S)-2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-4-oxobut-2-enamide(EXAMPLE 500, 2.9 mg, 0.0048 mmol, 120% yield). ESI+APCI MS m/z 609.3[M+H]⁺.

Example 501

(E)-4-((S)-2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-4-oxobut-2-enenitrile

Step A: Ethyl (E)-3-cyanoacrylate. Ethyl cis-(beta-cyano)acrylate (1.0g, 7.99 mmol) was diluted with ACN (30 mL), placed under nitrogen andheated to reflux for 3 days. The reaction was allowed to cool and thenconcentrated. The material was purified on silica gel eluting withhexanes to afford ethyl (E)-3-cyanoacrylate (300 mg, 2.40 mmol, 30.0%yield).

Step B: (E)-3-cyanoacrylic acid: Ethyl (E)-3-cyanoacrylate (10 mg, 0.080mmol) was diluted with HCl (133 μl, 0.80 mmol), placed under nitrogenand heated to 100° C. After stirring for 15 minutes the reaction wasconcentrated to afford (E)-3-cyanoacrylic acid (7.5 mg, 0.077 mmol, 97%yield).

Step C:(E)-4-((S)-2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-4-oxobut-2-enenitrile:2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(20 mg, 0.03909 mmol) and (E)-3-cyanoacrylic acid (5.312 mg, 0.05472mmol) were diluted with DMF (400 uL) followed by the addition of DIEA(13.65 μl, 0.07817 mmol) and 1-propanephosphonic acid cyclic anhydride(34.90 μl, 0.05863 mmol). After stirring for 12 hours, the reaction wasdiluted with ethyl acetate and saturated sodium bicarbonate. The layerswere separated and the ethyl acetate was dried over MgSO4, filtered andconcentrated. The material was purified on silica gel eluting with 10%methanol/DCM (1% NH4OH) to afford title compound(E)-4-((S)-2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-4-oxobut-2-enenitrile(EXAMPLE 501, 3.5 mg, 0.005925 mmol, 15.16% yield). ESI+APCI MS m/z591.3 [M+H]⁺.

Example 502

(Z)-4-((S)-2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-4-oxobut-2-enenitrile

Step A: (Z)-3-cyanoacrylic acid: Ethyl cis-(beta-cyano)acrylate (50 mg,0.40 mmol) was diluted with HCl (200 μl, 1.2 mmol), placed undernitrogen and heated to 100° C. After stirring for 1 minute the reactionwas cooled and concentrated to afford (Z)-3-cyanoacrylic acid (35 mg,0.36 mmol, 90% yield).

Step B:(Z)-4-((S)-2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-4-oxobut-2-enenitrile:2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(20 mg, 0.03909 mmol) and (Z)-3-cyanoacrylic acid (6.071 mg, 0.06254mmol) were diluted with DMF (400 uL) followed by the addition of DIEA(13.65 μl, 0.07817 mmol) and 1-propanephosphonic acid cyclic anhydride(39.56 μl, 0.06645 mmol). After stirring for 12 hours, the reaction wasdiluted with ethyl acetate and saturated sodium bicarbonate. The layerswere separated and the ethyl acetate was dried over MgSO4, filtered andconcentrated. The material was purified on silica gel eluting with 10%methanol/DCM (1% NH4OH) to afford title compound(Z)-4-((S)-2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-4-oxobut-2-enenitrile(EXAMPLE 502, 2.1 mg, 0.003555 mmol, 9.095% yield). ESI+APCI MS m/z591.3 [M+H]⁺.

Example 503

2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-(dimethylamino)-2-fluoro-but-2-enoyl]piperazin-2-yl]acetonitrile

Step 1: (E)-4-[tert-butoxycarbonyl(methyl)amino]-2-fluoro-but-2-enoicacid. To the solution of ethyl 2-diethoxyphosphoryl-2-fluoro-acetate (2g, 8.26 mmol, 1.68 mL, 1 eq) and tert butylN-methyl-N-(2-oxoethyl)carbamate (2.15 g, 12.4 mmol, 1.5 eq) in THF (40mL) was added NaH (661 mg, 16.5 mmol, 60% purity, 2 eq). The mixture wasstirred at 25° C. for 1.5 hour. Upon completion, the reaction mixturewas quenched by saturated NH₄Cl (8 mL) and concentrated under vacuum.The residue was purified by prep-HPLC (column: Phenomenex Synergi Max-RP250*50 mm*10 um; mobile phase: [water (0.225% FA)-ACN]; B %: 20 ACN %-50ACN %, 30 min; 50% min) to give(E)-4-[tert-butoxycarbonyl(methyl)amino]-2-fluoro-but-2-enoic acid (820mg, 3.16 mmol, 38.3% yield, 90% purity) as a brown oil.

Step A: tert-butylN-[(E)-4-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazin-1-yl]-3-fluoro-4-oxo-but-2-enyl]-N-methyl-carbamate.To a solution of2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(Intermediate 71, 300 mg, 564 umol, 1 eq),(E)-[tert-butoxycarbonyl(methyl)amino]-2-fluoro-but-2-enoic acid (600mg, 2.57 mmol, 4.56 eq) and DIEA (729 mg, 5.64 mmol, 982 uL, 10 eq) inDCM (10 mL) was added HATU (643 mg, 1.69 mmol, 3 eq) at 0° C. Thereaction mixture was stirred at 25° C. for 1 hour. Upon completion, thereaction mixture was quenched by water (3 mL) and extracted with DCM(3×8 mL). The combined organic layers were dried over Na₂SO₄ andconcentrated under vacuum. The residue was purified by reversed flashchromatography (FA condition: 60% MeCN in water (0.1% FA)) to givetert-butylN-[(E)-4-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazin-1-yl]-3-fluoro-4-oxo-but-2-enyl]-N-methyl-carbamate(330 mg, 404 umol, 72% yield, 91.5% purity) as a brown solid. LCMS [ESI,M+1]: 747.

Step B:2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-2-fluoro-4-(methylamino)but-2-enoyl]piperazin-2-yl]acetonitrile.To a solution of tert-butylN-[(E)-4-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazin-1-yl]-3-fluoro-4-oxo-but-2-enyl]-N-methyl-carbamate(300 mg, 401 umol, 1 eq) in DCM (1 mL) was added TFA (915 mg, 8.03 mmol,594 uL, 20 eq). The reaction mixture was stirred at 25° C. for 1 hour.Upon completion, the reaction mixture was diluted by DCM (10 mL) andbasified by saturated NaHCO₃ (8 mL). The mixture was extracted with DCM(3×10 mL). The combined organic layer was dried over Na₂SO₄ andconcentrated under vacuum to give2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-2-fluoro-4-(methylamino)but-2-enoyl]piperazin-2-yl]acetonitrile(240 mg, 356 umol, 89% yield, 95.9% purity) as a brown solid which wasused for next step without further purification. LCMS [ESI, M+1]: 647.

Step C:2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-(dimethylamino)-2-fluoro-but-2-enoyl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-2-fluoro-4-(methylamino)but-2-enoyl]piperazin-2-yl]acetonitrile(120 mg, 185 umol, 1 eq) and paraformaldehyde (83.5 mg, 927 umol, 5 eq),HCOOH (26.7 mg, 556 umol, 3 eq) in MeOH (5 mL) was added NaBH₃CN (35.0mg, 556 umol, 3 eq). The reaction mixture was stirred at 25° C. for 12hours. Upon completion, the reaction mixture was quenched by water (0.5mL) and filtered. The residue was purified by silica gel chromatography(EA:MeOH:NH₃·H₂O=50:1:0 to 10:1:0.1), then prep-HPLC (column: PhenomenexGemini 150*25 mm*10 um; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B %:50%-100%, 10 min) to give title compound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-(dimethylamino)-2-fluoro-but-2-enoyl]piperazin-2-yl]acetonitrile(EXAMPLE 503, 26.7 mg, 40.2 umol, 22% yield, 99.5% purity) as a yellowsolid. LCMS [ESI, M+1]: 661.

¹H NMR (400 MHz, chloroform-d) δ=7.68 (d, J=8.0 Hz, 1H), 7.54 (t, J=7.2Hz, 1H), 7.45 (d, J=7.2 Hz, 1H), 7.37 (td, J=7.6, 12.8 Hz, 1H), 7.26 (t,J=8.0 Hz, 1H), 7.19-7.08 (m, 1H), 5.81-5.60 (m, 1H), 5.04-4.41 (m, 1H),4.40-4.25 (m, 2H), 4.16-3.91 (m, 3H), 3.88-3.71 (m, 2H), 3.66-3.46 (m,2H), 3.36 (br d, J=10.8 Hz, 1H), 3.27-2.69 (m, 9H), 2.64-2.56 (m, 1H),2.55-2.46 (m, 1H), 2.40 (d, J=2.4 Hz, 3H), 2.27-2.15 (m, 7H), 2.06-1.90(m, 1H), 1.85-1.72 (m, 3H).

Example 504

2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[2-(trifluoromethyl)prop-2-enoyl]piperazin-2-yl]acetonitrile

Step A:2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[2-(trifluoromethyl)prop-2-enoyl]piperazin-2-yl]acetonitrile.To a solution of 2-(trifluoromethyl)prop-2-enoic acid (39.5 mg, 282umol, 1.50 eq),2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(Intermediate 71, 0.10 g, 188 umol, 1.00 eq) and DIEA (48.6 mg, 376umol, 65.5 uL, 2.00 eq) in dichloromethane (0.20 mL) was added HATU (107mg, 282 umol, 1.50 eq) at 0° C. After stirred at 0° C. for 0.5 h, themixture diluted with water and the layer was separated. The organiclayer was dried over Na₂SO₄, filtered and concentrated under vacuum. Theresidue was purified by reverse phase flash [water (FA,0.1%)/acetonitrile] and prep HPLC (column: Gemini 150*25 5 u; mobilephase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 56%-86%, 12 min).The desired fractions were collected and lyophilized to give titlecompound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[2-(trifluoromethyl)prop-2-enoyl]piperazin-2-yl]acetonitrile(EXAMPLE 504, 13.1 mg, 19.6 umol, 10.5% yield, 97.9% purity) as a whitesolid. LCMS [ESI, M+1]: 654.

SFC condition: Column: Chiralcel OJ-3 50×4.6 mm I.D., 3 um, Mobilephase: methanol (0.05% DEA) in CO₂ from 5% to 40%, Flow rate: 3 mL/min,Wavelength: 220 nm.

¹H NMR (400 MHz, chloroform-d) δ=7.76 (d, J=8.4 Hz, 1H), 7.65-7.59 (m,1H), 7.55-7.50 (m, 1H), 7.45 (td, J=7.6, 10.0 Hz, 1H), 7.34 (t, J=7.6Hz, 1H), 7.26-7.18 (m, 1H), 6.18 (br s, 1H), 5.86 (br s, 1H), 5.11 (brs, 1H), 4.57-4.36 (m, 2H), 4.33-4.10 (m, 2H), 4.04 (br d, J=12.8 Hz,1H), 3.97-3.79 (m, 2H), 3.66-3.54 (m, 1H), 3.50-3.33 (m, 1H), 3.29-3.07(m, 4H), 3.04-2.72 (m, 4H), 2.63-2.50 (m, 4H), 2.45-2.32 (m, 1H),2.15-2.04 (m, 1H), 1.90 (br s, 3H).

Example 505

2-((S)-1-((Z)-3-chloroacryloyl)-4-(7-(2,3-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-((S)-1-((Z)-3-chloroacryloyl)-4-(7-(2,3-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:Was prepared following Example 389 Step J, substituting(Z)-3-chloroacrylic acid for but-2-ynoic acid. ESI+APCI MS m/z 564.3[M+H]⁺.

Example 506

2-((S)-1-((E)-4-fluorobut-2-enoyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A:2-((S)-1-((E)-4-fluorobut-2-enoyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:At 0° C., to a 25 mL RBF containing N,N-dimethylfomamide (3909 μl, 0.39mmol) was added2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(200 mg, 0.391 mmol) and triethylamine (136 μl, 0.98 mmol). The reactionmixture was vigorously stirred while (E)-4-fluorobut-2-enoic acid (61.0mg, 0.59 mmol) was added in one portion. Next, 1-propanephosphonic acidcyclic anhydride (175 μl, 0.59 mmol) was added slowly to the stirringmixture. The reaction was stirred at room temperature for 18 hr. Waterwas added and the mixture was extracted with EtOAc (3×15 mL). Theextracts were combined and washed with water (1×10 mL) and concentrated.The residue was purified by silica gel (5-18% MeOH in DCM with 0.25%NH₄OH) to provide title compound2-((S)-1-((E)-4-fluorobut-2-enoyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(EXAMPLE 506, 89.3 mg, 0.15 mmol, 38% yield). ESI+APCI MS m/z 598.3[M+H]⁺.

Example 507

2-((S)-1-(2-fluoroacryloyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A:2-((S)-1-(2-fluoroacryloyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(8 g, 15.63 mmol) was diluted with DMF (78.17 ml, 15.63 mmol), placedunder nitrogen and cooled to 0° C. DIEA (6.827 ml, 39.09 mmol) was addedfollowed by the addition of 2-Fluoroacrylic acid (2.112 g, 23.45 mmol)and the dropwise addition of 1-Propanephosphonic acid cyclic anhydride(9.307 ml, 15.63 mmol). The reaction was stirred at 0° C. for 6 hoursand left to stir for an additional 10 hours warming to ambienttemperature. The reaction was poured into a 5% sodium bicarbonatesolution and extracted twice with ethyl acetate. The ethyl acetate waswashed with water, brine, dried over MgSO4, filtered and concentrated.The material was purified on silica gel eluting with 1-10% methanol/DCM(1% NH4OH as additive) to afford title compound2-((S)-1-(2-fluoroacryloyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(EXAMPLE 507, 6.6 g, 11.31 mmol, 72.32% yield). ESI+APCI MS m/z 584.3[M+H]⁺.

Example 508

2-((S)-1-(4-hydroxybut-2-ynoyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-((S)-1-(4-hydroxybut-2-ynoyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:was prepared according to Example 458, Step D, substituting4-((tert-butyldimethylsilyl)oxy)but-2-ynoic acid for but-2-ynoic acidESI+APCI MS m/z 594.3 [M+H]⁺.

Example 509

2-((S)-1-((E)-4-(1H-pyrazol-1-yl)but-2-enoyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: (E)-4-(1H-pyrazol-1-yl)but-2-enoic acid. A solution of4-bromocrotonic acid (100 mg, 0.606 mmol) and pyrazole (37.1 mg, 0.546mmol) in acetonitrile (1 ml, 19.1 mmol) was heated in a closed vial for48 h to 60° C. with stirring. The resulted light-green solution wasdivided between water (5 mL) and EtOAc (15 mL), the organics wereseparated, the organic layer was washed with brine, dried over Na₂SO₄and evaporated in vacuo. The material was chromatographed on silica gelin 2 to 5% MeOH/DCM+0.2% TFA. The resulting solid was dissolved inminimal amount of 6M HCl and evaporated under slow N₂ flow. Thismaterial was used in the next step without further purification.

Step B:2-((S)-1-((E)-4-(1H-pyrazol-1-yl)but-2-enoyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.A stirred mixture of2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(42.37 mg, 0.08281 mmol), (E)-4-(1H-pyrazol-1-yl)but-2-enoic acid (12.6mg, 0.08281 mmol) and N,N-dimethylformamide (1 mL, 12.79 mmol) wascooled on ice-salt bath with stirring, and triethylamine (0.03463 mL,0.2484 mmol) was added at once, followed by2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide, 50% inEtOAc (0.07395 mL, 0.1242 mmol). The reaction mixture was allowed towarm up to r.t. over 5 min and was stirred at r.t. overnight. Thereaction mixture was divided between 0.5M Na₂CO₃ (5 mL) and EtOAc (10mL), the organics were separated, the organic layer was washed withwater and brine (5 mL each), dried over Na₂SO₄ and evaporated in vacuo.The product was purified by silica gel chromatography using 5% MeOH+0.5%NH₄OH in DCM to give title compound as a colorless solid (EXAMPLE 509,11.46 mg, 23%). ESI+APCI MS m/z 646.3 [M+H]⁺.

Example 510

2-((S)-1-((E)-4-hydroxybut-2-enoyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: (E)-4-hydroxybut-2-enoic acid. To a stirred suspension of4-bromocrotonic acid (4824 mg, 29.24 mmol) in water (48 mL) a 2Msolution of potassium hydroxide (4.921 g, 87.72 mmol) was added dropwiseand the resulted solution was heated to reflux for 5 min. The reactionmixture was left under a N₂ stream to cool and concentrate. The residuewas cooled on ice bath, acidified with 4M H₂SO₄ to pH 1-2, the resultedsuspension was evaporated in vacuo by half and then extracted with EtOAc(3*60 mL). The combined extracts were dried over Na₂SO₄ and evaporatedin vacuo. The material was purified by chromatography using 2 to 5%MeOH+0.2% TFA to afford the target acid as colorless crystals (2.165 g,73%).

Step B:2-((S)-1-((E)-4-hydroxybut-2-enoyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.To a stirred solution of2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(100 mg, 0.1954 mmol), (2E)-4-hydroxybut-2-enoic acid (39.90 mg, 0.3909mmol) and N-ethyl-N-isopropylpropan-2-amine (0.06809 ml, 0.3909 mmol) inDCM (5 mL), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-Tetramethyluroniumhexafluorophosphate (111.5 mg, 0.2932 mmol) was added at once and thereaction mixture was stirred at r.t for 4 h. Water (1 mL) was added, thereaction mixture was stirred for 5 min and divided between EtOAc (10 mL)and sat. NaHCO₃ (5 mL). The organic layer was separated, washed withNaHCO₃, brine (5 mL each), dried over K₂CO₃ and evaporated in vacuo. Theresidue was chromatographed on silica gel with 5% MeOH+0.5% NH₄OH. Titlecompound as a colorless solid (EXAMPLE 510, 29 mg, 25%). ESI+APCI MS m/z596.3 [M+H]⁺.

Example 511

2-((S)-1-((E)-4-methoxybut-2-enoyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A:2-((S)-1-((E)-4-methoxybut-2-enoyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.A stirred mixture of2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(250 mg, 0.4886 mmol), (E)-4-methoxybut-2-enoic acid (85.10 mg, 0.7329mmol) and N,N-dimethylformamide (2 mL, 25.58 mmol) was cooled on anice-salt bath and triethylamine (0.2043 mL, 1.466 mmol) was added atonce, followed by 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane2,4,6-trioxide, 50% in EtOAc (0.4363 mL, 0.7329 mmol). The reactionmixture was allowed to warm to r.t. over 5 min. and stirred at r.t. for2 h. The resulted solution was divided between 0.5M Na₂CO₃ (10 mL) andEtOAc (30 mL), the organic layer was separated, washed with water andbrine (10 mL each), dried over Na₂SO₄ and evaporated in vacuo. Thematerial was purified by silica gel chromatography using 5% MeOH+0.5%NH₄OH in DCM. The material was further purified by the reverse phasechromatography, Gilson, 25 to 75% MeCN/H₂O+0.1% TFA. Target fractionswere basified with excess of 2M Na₂CO₃ and extracted with DCM (3*50 mL).The combined organic extracts were washed with brine, dried over Na₂SO₄and evaporated in vacuo. Title compound as a light-yellow solid (EXAMPLE511, 123 mg, 41%). ESI+APCI MS m/z 610.3 [M+H]⁺.

Example 512

2-[(2S)-1-(2-methoxyprop-2-enoyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

Step A: methyl 2,2-dimethoxypropanoate. To a solution of ethyl2-oxopropanoate (4.00 g, 34.5 mmol, 3.81 mL, 1.00 eq) andtrimethoxymethane (4.75 g, 44.8 mmol, 4.91 mL, 1.30 eq) in methanol(10.0 mL) was added H₂SO₄ (33.8 mg, 344 umol, 18.4 uL, 0.01 eq). Afterstirred at 65° C. for 4 hours, the pH value was adjusted >7 by KOH (120mg in 20.0 mL water) and extracted with ethyl acetate (3×20.0 mL). Theorganic layer was washed with brine (1×30.0 mL), dried over Na₂SO₄,filtered and concentrated under vacuum. The residue was distilled at 60°C. under oil pump to give methyl 2,2-dimethoxypropanoate (4.00 g, 27.0mmol, 78% yield) as a colourless oil and used into next step withoutfurther purification.

¹H NMR (400 MHz, chloroform-d) δ=3.81 (s, 3H), 3.28 (s, 6H), 1.52 (s,3H).

Step B: methyl 2-methoxyprop-2-enoate. To a solution of methyl2,2-dimethoxypropanoate (2.00 g, 13.5 mmol, 1.00 eq) in DMF (20.0 mL)was added P₂O₅ (1.05 g, 7.42 mmol, 458 uL, 0.55 eq) in portions. Afterheated to 100° C. for 1 hour, the mixture was diluted with saturatedsodium bicarbonate (20.0 mL), extracted with isopropyl ether (3×30.0mL), washed with brine (3×40.0 mL), dried over Na₂SO₄, filtered andconcentrated under vacuum. The residue was distilled under oil pump togive methyl 2-methoxyprop-2-enoate (0.65 g, 5.60 mmol, 41% yield) as acolorless oil and used into next step without further purification.

Step C: 2-methoxyprop-2-enoic acid. A mixture of methyl2-methoxyprop-2-enoate (0.60 g, 5.17 mmol, 1.00 eq) and NaOH (827 mg,20.7 mmol, 4.00 eq) in H₂O (5.00 mL) and THF (5.00 mL) was stirred at60° C. for 1 hour. The mixture was adjusted to pH<3 by concentrated HCl(10.0 mL) and extracted with ethyl acetate (3×20.0 mL). The organiclayer was dried over Na₂SO₄, filtered and concentrated under vacuum togive 2-methoxyprop-2-enoic acid (0.40 g, 1.96 mmol, 38% yield, 50%purity) as a pink oil and used into next step without furtherpurification.

¹H NMR (400 MHz, chloroform-d) δ=8.63 (br s, 1H), 5.52 (d, J=2.8 Hz,1H), 4.75 (d, J=2.8 Hz, 1H), 3.70 (s, 3H).

Step D:2-[(2S)-1-(2-methoxyprop-2-enoyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(0.14 g, 274 umol, 1.00 eq), 2-methoxyprop-2-enoic acid (112 mg, 1.09mmol, 4.00 eq) and DIEA (141 mg, 1.09 mmol, 191 uL, 4.00 eq) indichloromethane (5.00 mL) was added HATU (208 mg, 547 umol, 2.00 eq) at0° C. After stirred at 0° C. for 0.5 h, the mixture was diluted withwater (3.00 mL). The organic layer was dried over Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by reverse phaseflash [water (FA, 0.10%)/acetonitrile] and prep-HPLC (column: Gemini150*25 5 u, mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 60%-90%, 12 min). The desired fraction was collected and lyophilizedto give title compound2-[(2S)-1-(2-methoxyprop-2-enoyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(EXAMPLE 512, 10.27 mg, 17.22 umol, 6.3% yield, 99.9% purity) as aoff-white solid. LCMS [ESI, M+1]: 596.

SFC condition: “IC-3S_3_40_3 ML Column: Chiralpak IC-3 100×4.6 mm I.D.,3 um, Mobile phase: 40% methanol (0.05% DEA) in CO₂, Flow rate: 3mL/min, Wavelength: 220 nm”.

¹H NMR (400 MHz, chloroform-d) δ=7.72-7.61 (m, 2H), 7.45-7.31 (m, 2H),7.27-7.17 (m, 2H), 5.05-4.61 (m, 1H), 4.48 (br s, 1H), 4.37 (td, J=4.4,10.0 Hz, 1H), 4.30-3.98 (m, 4H), 3.96-3.74 (m, 2H), 3.69 (br s, 3H),3.59-3.28 (m, 2H), 3.27-2.93 (m, 6H), 2.92 (s, 3H), 2.88-2.51 (m, 4H),2.47 (d, J=3.2 Hz, 3H), 2.33-2.23 (m, 1H), 2.11-1.98 (m, 1H), 1.89-1.74(m, 3H).

Example 513

2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-hydroxybut-2-enoyl]piperazin-2-yl]acetonitrile

Step 1: ethyl (E)-4-hydroxybut-2-enoate. To a solution of(E)-4-ethoxy-4-oxo-but-2-enoic acid (1.0 g, 7.29 mmol, 1.0 eq) in THF(6.0 mL) was added a solution of BH₃-Me₂S (10.0 M, 692 uL, 0.95 eq) inTHF (8.0 mL) dropwise over 1 hour at −10° C. The reaction mixture wasgradually warmed to 25° C. and stirred for 17 hours. After completion,the reaction mixture was quenched by addition water (30.0 mL) andextracted with Ethyl acetate (30.0 mL×3). The combined organic layerswere washed with brine (30.0 mL×2), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. Compound ethyl(E)-4-hydroxybut-2-enoate (900 mg, crude) was obtained as colorless oil.The crude product was used directly in the next step without furtherpurification.

Step 2: (E)-4-trityloxybut-2-enoate. A mixture of ethyl(E)-4-hydroxybut-2-enoate (900 mg, crude),[chloro(diphenyl)methyl]benzene (2.89 g, 10.4 mmol), DMAP (84.5 mg, 692umol), TEA (1.4 g, 13.8 mmol, 1.9 mL) in DCM (5.0 mL) was degassed andpurged with N₂ for 3 times, and then the mixture was stirred at 25° C.for 1 hour under N₂ atmosphere. After completion, the reaction mixturewas quenched by addition H₂O (10.0 mL) and extracted with Ethyl acetate(10.0 mL×3). The combined organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=20:1 to 15:1). Compound ethyl(E)-4-trityloxybut-2-enoate (340 mg, 913 umol, 13% yield) was obtainedas colorless oil.

¹H NMR (400 MHz, Chloroform-d) δ 7.38-7.35 (m, 6H), 7.26-7.22 (m, 6H),7.18-7.15 (m, 3H), 6.88 (dt, J=15.6, 3.6 Hz, 1H), 6.29 (dt, J=15.6, 2.2Hz, 1H), 4.16 (q, J=7.1 Hz, 2H), 3.72 (dd, J=2.4, 2.0 Hz, 2H), 1.25 (t,J=7.0 Hz, 3H).

Step 3: (E)-4-trityloxybut-2-enoic acid. To a solution of ethyl(E)-4-trityloxybut-2-enoate (170 mg, 456 umol, 1.0 eq) in MeOH (1.0 mL)was added solution of NaOH (54.5 mg, 1.37 mmol, 3.0 eq) in H₂O (0.5 mL)and then the mixture was stirred at 40° C. for 1 hour under N₂atmosphere. After completion, the reaction mixture was quenched byaddition 1M HCl at 0° C. until pH=5, and then extracted with Ethylacetate (8.0 mL×3). The combined organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=3:1 to 1:1). Compound (E)-4-trityloxybut-2-enoicacid (113 mg, 328 umol, 72% yield) was obtained as a white solid.

¹H NMR (400 MHz, Chloroform-d) δ 7.38-7.36 (m, 6H), 7.26-7.24 (m, 5H),7.20-7.16 (m, 4H), 7.0 (dt, J=15.6, 3.6 Hz, 1H), 6.32 (dt, J=15.6, 2.0Hz, 1H), 3.76 (dd, J=3.2, 2.4 Hz, 2H).

Step A:2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-trityloxybut-2-enoyl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(Intermediate 71, 60.0 mg, 113 umol, 1.0 eq), (E)-4-trityloxybut-2-enoicacid (77.8 mg, 226 umol, 2.0 eq) and DIEA (73.0 mg, 564 umol, 98 uL, 5.0eq) in DCM (2.0 mL) was added HATU (64 mg, 169 umol, 1.5 eq) in oneportion at 0° C. under N₂. The mixture was stirred at 25° C. for 1 hour.After completion, the reaction mixture was quenched by addition H₂O (8.0mL) and then extracted with Ethyl acetate (10.0 mL×3). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. Compound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-trityloxybut-2-enoyl]piperazin-2-yl]acetonitrile(150 mg, crude) was obtained as a yellow solid, and the crude productwas used directly in the next step without further purification. LCMS[ESI, M+1]: 858.

Step B:2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-hydroxybut-2-enoyl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-trityloxybut-2-enoyl]piperazin-2-yl]acetonitrile(150 mg, crude) in DCM (1.0 mL) was added TFA (1.0 ml, 13.5 mmol). Themixture was stirred at 25° C. for 1 hour. After completion, the reactionmixture was quenched by addition NaHCO₃ aqueous solution at 0° C. untilpH=8, and then extracted with Ethyl acetate (10.0 mL×3). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified byprep-HPLC (column: Phenomenex Gemini 150*25 mm*10 um; mobile phase:[water (0.04% NH₃H₂O+10 mM NH₄HCO₃)-ACN]; B %: 48%-72%, 10 min.) andlyophilization. Tide compound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-hydroxybut-2-enoyl]piperazin-2-yl]acetonitrile(EXAMPLE 513, 8.21 mg, 13.3 umol, 7.6% yield. 99.8% purity) was obtainedas a white solid. LCMS [ESI, M+1]: 616.

SFC condition: 100% e.e.

¹H NMR (400 MHz, Chloroform-d) δ 7.68 (d, J=8.0 Hz, 1H), 7.70-7.33 (m,1H), 7.49 (dd, J=6.8, 0.8 Hz, 1H), 7.37 (dt, J=11.98, 7.82 Hz, 1H), 7.26(t, J=11.8 Hz, 1H), 7.19-7.11 (m, 1H), 6.99 (dt, J=14.8, 3.4 Hz, 1H),6.56 (br s, 1H), 5.02-4.57 (m, 1H), 4.39-4.29 (m, 4H), 4.12-4.06 (m,1H), 4.03-3.99 (m, 2H), 3.85-3.72 (m, 2H), 3.67-3.36 (m, 3H), 3.24-3.09(m, 2H), 3.03-2.89 (m, 3H), 2.73 (br s, 1H), 2.63-2.61 (m, 1H), 2.50 (brs, 1H), 2.41 (s, 3H), 2.25-2.19 (m, 1H), 2.03-1.92 (m, 1H), 1.70-1.60(m, 3H).

Example 514

2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-methoxyprop-2-enoyl)piperazin-2-yl]acetonitrile

Step 1: methyl 2,2-dimethoxypropanoate. To a solution of ethyl2-oxopropanoate (4.00 g, 34.5 mmol, 3.81 mL, 1.00 eq) andtrimethoxymethane (4.75 g, 44.8 mmol, 4.91 mL, 1.30 eq) in methanol(10.0 mL) was added H₂SO₄ (33.8 mg, 344 umol, 18.4 uL, 0.01 eq). Afterstirring at 65° C. for 4 hours, the reaction mixture was adjusted to pHvalue was adjusted >7 by KOH aqueous (120 mg in 20.0 mL water) andextracted with ethyl acetate (3×20.0 mL). The organic layers were washedwith brine (1×30.0 mL), dried over Na₂SO₄, filtered and concentratedunder vacuum. The residue was distilled at 60° C. under vacuum to givemethyl 2,2-dimethoxypropanoate (4.00 g, 27.0 mmol, 78% yield) as acolorless oil.

¹H NMR (400 MHz, chloroform-d) δ=3.81 (s, 3H), 3.28 (s, 6H), 1.52 (s,3H).

Step 2: methyl 2-methoxyprop-2-enoate. To a solution of methyl2,2-dimethoxypropanoate (2.00 g, 13.5 mmol, 1.00 eq) in DMF (20.0 mL)was added P₂O₅ (1.05 g, 7.42 mmol, 458 uL, 0.55 eq) in portions. Afterstirring at 100° C. for 1 hour, the mixture was diluted with saturatedsodium bicarbonate (20.0 mL), extracted with isopropyl ether (3×30.0mL). The extracts were washed with brine (3×40.0 mL), dried over Na₂SO₄,filtered and concentrated under vacuum. The residue was distilled undervacuum to give methyl 2-methoxyprop-2-enoate (0.65 g, 5.60 mmol, 41%yield) as a colorless oil which was used to next step without furtherpurification.

¹H NMR (400 MHz, chloroform-d) δ=5.36 (d, J=2.8 Hz, 1H), 4.63 (d, J=2.8Hz, 1H), 3.81 (s, 3H), 3.66 (s, 3H).

Step 3: 2-methoxyprop-2-enoic acid. A mixture of methyl2-methoxyprop-2-enoate (0.60 g, 5.17 mmol, 1.00 eq) and NaOH (827 mg,20.7 mmol, 4.00 eq) in H₂O (5.00 mL) and THF (5.00 mL) was stirred at60° C. for 1 hour. The mixture was adjusted to pH<3 by concentrated HCl(10.0 mL) and extracted with ethyl acetate (3×20.0 mL). The organiclayer was dried over Na₂SO₄, filtered and concentrated under vacuum togive 2-methoxyprop-2-enoic acid (0.40 g, 1.96 mmol, 38% yield, 50%purity) as a pink oil and used into next step without furtherpurification.

¹H NMR (400 MHz, chloroform-d) δ=8.63 (br s, 1H), 5.52 (d, J=2.8 Hz,1H), 4.75 (d, J=2.8 Hz, 1H), 3.70 (s, 3H).

Step A: 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-methoxyprop-2-enoyl)piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(0.20 g, 376 umol, 1.00 eq), 2-methoxyprop-2-enoic acid (153 mg, 1.50mmol, 4.00 eq) and DIEA (194 mg, 1.50 mmol, 262 uL, 4.00 eq) indichloromethane (5.00 mL) was added HATU (286 mg, 752 umol, 2.00 eq) at0° C. Ater stirred at 0° C. for 0.5 h, the reaction was purified byreversed phase flash [water (FA, 0.1%)/acetonitrile, prep-HPLC (column:Luna C18 150*25 5 u; mobile phase: (water (0.225% FA)-ACN], B %:25%-45%, 7.8 min) and further prep-HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %:55%-79%, 10 min). The desired fractions were collected and lyophilizedto give title compound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-methoxyprop-2-enoyl)piperazin-2-yl]acetonitrile(EXAMPLE 514, 30.1 mg, 48.9 umol, 13% yield, 100% purity) as a yellowsolid. LCMS [ESI, M+1]: 616.

SFC condition: “AS-3_MeOH (DEA)_5_40_3 mL-35T Column: Chiralpak AS-350×4.6 mm I.D., 3 um, Mobile phase: methanol (0.05% DEA) in CO₂ from 5%to 40%, Flow rate: 3 mL/min, Wavelength: 220 nm”.

¹H NMR (400 MHz, chloroform-d) δ=7.76 (br d, J=8.0 Hz, 1H), 7.62 (t,J=7.6 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 7.44 (td, =7.6, 13.6 Hz, 1H),7.34 (t, J=8.0 Hz, 1H), 7.27-7.18 (m, 1H), 5.07-4.63 (m, 1H), 4.57-4.29(m, 4H), 4.21-3.96 (m, 3H), 3.95-3.77 (m, 2H), 3.69 (br s, 3H), 3.59 (brd, J=11.2 Hz, 1H), 3.51-3.32 (m, 1H), 3.30-3.02 (m, 5H), 2.89-2.50 (m,4H), 2.47 (d, J=2.0 Hz, 3H), 2.32-2.23 (m, 1H), 2.11-2.00 (m, 1H),1.89-1.72 (m, 3H).

Example 15

2-[(2S)-1-[(E)-4-(3-fluoroazetidin-1-yl)but-2-enoyl]-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

Step A:2-[(2S)-1-[(E)-4-bromobut-2-enoyl]-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(150 mg, 293 umol, 1.0 eq) and pyridine (186 mg, 2.35 mmol, 189 uL, 8.0eq) in dichloromethane (4.0 mL) was added (E)-4-bromobut-2-enoylchloride (215 mg, 1.17 mmol, 4.0 eq). The mixture was stirred at 0° C.for 0.5 hour. After completion, the reaction mixture was concentrated togive the product2-[(2S)-1-[(E)-4-bromobut-2-enoyl]-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(200 mg, crude) as yellow oil. The product was used for the next stepwithout further purification. LCMS [ESI, M+1]: 658.

Step B:2-[(2S)-1-[(E)-4-(3-fluoroazetidin-1-yl)but-2-enoyl]-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-1-[(E)-4-bromobut-2-enoyl]-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(150 mg, 228 umol, 1.0 eq) and K₂CO₃ (315 mg, 2.28 mmol, 10.0 eq) inacetonitrile (2.0 mL) was added 3-fluoroazetidine (152 mg, 1.37 mmol,6.0 eq, HCl). The mixture was stirred at 0° C. for 0.5 hour. Aftercompletion, the reaction mixture was added water (5.0 mL) and extractedwith ethyl acetate (5.0 mL×4). The organic layer was dried over Na₂SO₄,filtered and concentrated under vacuum. The residue was purified byprep-HPLC (column: Gemini 150*25 5 u; mobile phase: [water (0.05%ammonia hydroxide v/v)-ACN]; B %: 60%-90%, 12 min) to give the titlecompound2-[(2S)-1-[(E)-4-(3-fluoroazetidin-1-yl)but-2-enoyl]-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(EXAMPLE 515, 45.0 mg, 66 umol, 29% yield, 96% purity) as white solid.LCMS [ESI, M+1]: 653.

¹H NMR (400 MHz, Chloroform-d) δ 7.70 (br d, J=8.0 Hz, 1H), 7.65 (t,J=8.4 Hz, 1H), 7.41 (dd, J=7.6, 15.2 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H),7.27-7.18 (m, 2H), 6.92-6.82 (m, 1H), 6.52-6.31 (m, 1H), 5.28-5.08 (m,1H), 5.07-4.46 (m, 1H), 4.41-4.33 (m, 1H), 4.32-4.01 (m, 4H), 4.01-3.79(m, 2H), 3.79-3.56 (m, 3H), 3.55-3.37 (m, 2H), 3.36-3.31 (m, 2H),3.30-3.24 (m, 1H), 3.23-3.18 (m, 2H), 3.17-3.15 (m, 1H), 3.14-3.06 (m,2H), 3.05-2.95 (m, 1H), 2.92 (s, 3H), 2.86-2.75 (m, 1H), 2.71-2.57 (m,2H), 2.47 (d, J=4.0 Hz, 3H), 2.33-2.22 (m, 1H), 2.11-1.99 (m, 1H),1.88-1.67 (m, 3H).

Example 516

2-((S)-1-(2-fluoroacryloyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((R)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: tert-Butyl4-[(3S)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate.A mixture of tert-butyl4-[(3S)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(5.5 g, 10.4 mmol, 1 eq), [(2R)-1-methylpyrrolidin-2-yl]methanol (2.40g, 20.9 mmol, 2.25 mL, 2 eq), Pd₂(dba)₃ (1.91 g, 2.09 mmol, 0.2 eq),RuPhos (1.95 g, 4.17 mmol, 0.4 eq) and Cs₂CO₃ (8.50 g, 26.1 mmol, 2.5eq) in toluene (100 mL) was degassed and purged with N₂ for 3 times, andthen the mixture was stirred at 90° C. for 5 hours under N₂ atmosphere.The reaction mixture was concentrated under reduced pressure to give aresidue. The residue was diluted with ethyl acetate (100 mL) and water(50 mL). Then the mixture was acidified to PH˜ 4 with 1 M HCl aqueoussolution. The water phase was separated and basified to PH˜8 withsaturated Na₂CO₃ aqueous solution, then the mixture was extracted withethyl acetate (50 mL×2). The combined organic layers were washed withbrine (30 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure. tert-Butyl4-[(3S)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(4 g, 5.55 mmol, 53% yield, 84% purity) was obtained as a yellow solidand used to next step without purification.

¹H NMR (400 MHz, chloroform-d) δ=7.46-7.31 (m, 5H), 5.23 (s, 2H),4.74-4.49 (m, 2H) 4.43-4.27 (m, 2H), 4.21-3.70 (m, 5H), 3.42-3.17 (m,3H), 3.09 (t, J=7.6 Hz, 1H), 2.98 (td, J=3.6, 12.4 Hz, 1H), 2.86-2.74(m, 1H), 2.74-2.54 (m, 4H), 2.47 (s, 3H), 2.35-2.21 (m, 1H), 2.05-1.97(m, 1H), 1.90-1.74 (m, 3H), 1.49 (s, 9H).

Step B: benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of tert-butyl4-[(3S)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(3.7 g, 6.11 mmol, 1 eq) in dioxane (20 mL) was added HCl/dioxane (4 M,22.9 mL, 15 eq). The mixture was stirred at 0° C. for 1 hour. The liquidwas decanted and the solid was collected. The solid residue was dilutedwith water (50 mL) and dichloromethane (100 mL), then the mixture wasbasified to pH˜8 with saturated Na₂CO₃ aqueous solution and extractedwith dichloromethane (100 mL×3). The combined organic layers were washedwith brine (50 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure. Benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(2.6 g, 4.89 mmol, 80% yield, 95% purity) was obtained as a yellow solidand used next step without purification. LCMS [ESI, M+1]: 506.

Step C: benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.A mixture of benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(2.3 g, 4.55 mmol, 1 eq), 1-bromo-8-methyl-naphthalene (Intermediate 69,1.31 g, 5.91 mmol, 1.3 eq), Cs₂CO₃ (3.71 g, 11.4 mmol, 2.5 eq),Pd₂(dba)₃ (833 mg, 909 umol, 0.2 eq) and Xantphos (1.05 g, 1.82 mmol,0.4 eq) in toluene (50 mL) was degassed and purged with N₂ for 3 times,and then the mixture was stirred at 90° C. for 6 hours under N₂atmosphere. The reaction mixture was diluted with water (100 mL) andextracted with ethyl acetate (200 mL×3). The combined organic layerswere washed with brine (100 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by column chromatography (SiO₂, Ethyl acetate/Methanol 100/1 to10/1). Benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1.6 g, 2.48 mmol, 54% yield) was obtained as a yellow solid.

Step D:2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.A mixture of benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1.60 g, 2.48 mmol, 1.00 eq) in MeOH (20.0 mL) and NH₃ (20% w/w in MeOH,7 mL) was hydrogenated with Pd/C (100 mg, 2.48 mmol, 10% purity, 1.00eq) as a catalyst under H₂ (4.99 mg, 2.48 mmol, 1.00 eq, 15 psi) at 25°C. for 3 hours. The catalyst was filtered off through a pad of celiteand the filtrate was concentrated under vacuum. The crude product wasused to next step directly without further purification.2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(1.20 g, 2.35 mmol, 95% yield) was obtained as a light yellow solid.LCMS [ESI, M+1]: 512.

Step E:2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a mixture of2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(140 mg, 274 umol, 1.00 eq) and 2-fluoroprop-2-enoic acid (73.9 mg, 821umol, 3.00 eq) in dichloromethane (3.00 mL) was added DIEA (212 mg, 1.64mmol, 286 uL, 6.00 eq), HATU (312 mg, 821 umol, 3.00 eq) in one portionat 0° C. under N₂. After stirring at 0° C. for 30 min, the reactionmixture was diluted with water (10.0 mL) and extracted withdichloromethane (2×10.0 mL). The combined organic layers were washedwith water (1×10.0 mL), dried over sodium sulfate, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by prep-HPLC (column: Phenomenex Gemini 150*25 mm*10 um; mobilephase: [water (0.04% NH₃H₂O+10 mM NH₄HCO₃)-ACN]; B %: 55%-85%, 10 min).Title compound2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(EXAMPLE 516, 48.7 mg, 82.1 umol, 30% yield, 98.4% purity) was obtainedas a white solid.

SFC condition: “Column: Chiralcel OJ-3 50×4.6 mm I.D., 3 um, Mobilephase: methanol (0.05%” DEA) in CO₂ from 5% to 40%, Flow rate: 3 mL/min,Wavelength: 220 nm”.

¹H NMR (400 MHz, chloroform-d) δ=7.73-7.62 (m, 2H), 7.45-7.31 (m, 2H),7.27-7.17 (m, 2H), 5.53-5.34 (m, 1H), 5.26 (dd, J=3.6, 17.2 Hz, 1H),4.88 (br s, 1H), 4.41-4.32 (m, 1H), 4.31-4.22 (m, 1H), 4.21-4.10 (m,2H), 4.10-4.02 (m, 1H), 3.89 (br d, J=18.0 Hz, 1H), 3.78 (d, J=18.4 Hz,1H), 3.59-3.40 (m, 2H), 3.27-3.15 (m, 2H), 3.14-3.04 (m, 2H), 3.03-2.90(m, 4H), 2.90-2.73 (m, 2H), 2.72-2.56 (m, 2H), 2.47 (d, J=4.8 Hz, 3H),2.33-2.23 (m, 1H), 2.11-1.98 (m, 1H), 1.90-1.74 (m, 3H).

Example 517

2-((S)-1-((E)-4-hydroxybut-2-enoyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((R)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A:2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-trityloxybut-2-enoyl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(120 mg, 234 umol, 1 eq), TEA (142 mg, 1.41 mmol, 195 uL, 6 eq) and(E)-4-trityloxybut-2-enoic acid (96.9 mg, 281 umol, 1.2 eq) in ethylacetate (2 mL) was added T3P (448 mg, 703 umol, 418 uL, 50% purity inEtOAc, 3 eq) at 0° C. The mixture was stirred at 0° C. for 0.5 hour. Thereaction mixture was diluted with water (5 mL) and extracted with ethylacetate (10 mL×3). The combined organic layers were washed with brine(10 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue. The residue was purified by columnchromatography (SiO₂, Ethyl acetate/Methanol=200/1 to 10/1).2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-trityloxybut-2-enoyl]piperazin-2-yl]acetonitrile(90 mg, 103 umol, 44% yield, 96% purity) was obtained as a yellow oil.LCMS [ESI, M+1]: 838.

Step B:2-[(2S)-1-[(E)-4-hydroxybut-2-enoyl]-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-trityloxybut-2-enoyl]piperazin-2-yl]acetonitrile(80 mg, 95.5 umol, 1 eq) in dichloromethane (200 uL) was added TFA (218mg, 1.91 mmol, 141 uL, 20 eq). The mixture was stirred at 0° C. for 1hour. The reaction mixture was diluted with water (5 mL) and basified topH˜8 with NaHCO₃=aqueous solution (2 mL). The mixture was extracted withdichloromethane (5 mL×3). The combined organic layers were washed withbrine (3 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue. The residue was purified by prep-HPLC(column: Gemini 150*25 5 u; mobile phase-[water (0.05% ammonia hydroxidev/v)-ACN]; B %: 50%-80%, 12 min). The mixture was collected andlyophlizated. Title compound2-[(2S)-1-[(E)-4-hydroxybut-2-enoyl]-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(EXAMPLE 517, 10.2 mg, 16.8 umol, 18% yield, 98.5% purity) was obtainedas a off-white solid. LCMS [ESI, M+1]: 596.

SFC condition: Column: Chiralcel OD-3 50×4.6 mm I.D., 3 um, Mobilephase: 40% methanol (0.05% DEA) in CO₂, Flow rate: 3 mL/min, Wavelength:220 nm.

¹H NMR (400 MHz, chloroform-d) δ=7.73-7.61 (m, 2H), 7.46-7.30 (m, 2H),7.27-7.16 (m, 2H), 7.06 (d, J=14.8 Hz, 1H), 6.62 (br d, J=13.6 Hz, 1H),5.25-4.53 (m, 1H), 4.48-4.32 (m, 3H), 4.30-3.95 (m, 4H), 3.93-3.82 (m,1H), 3.81-3.61 (m, 1H), 3.59-3.39 (m, 2H), 3.30-2.96 (m, 5H), 2.92 (s,3H), 2.87-2.53 (m, 4H), 2.47 (d, J=4.0 Hz, 3H), 2.34-2.21 (m, 1H),2.13-1.99 (m, 1H), 1.98-1.82 (m, 3H).

Example 518

2-[(2S)-4-[2-[[(2R,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile

Step 1: O1-tert-butyl O2-methyl(2R,4R)-4-fluoropyrrolidine-1,2-dicarboxylate. To a solution of(2R,4R)-1-tert-butoxycarbonyl-4-fluoro-pyrrolidine-2-carboxylic acid(300 mg, 1.29 mmol, 1.0 eq) and K₂CO₃ (533 mg, 3.86 mmol, 3.0 eq) in DMF(2.0 mL) was added MeI (4.80 g, 33.8 mmol, 2.11 mL, 26.3 eq). Themixture was stirred at 20° C. for 12 hours. After completion, thereaction mixture was added water (5.0 mL) and extracted with ethylacetate (10.0 mL×2). The organic layer was dried over Na₂SO₄, filteredand concentrated. The residue was purified by column chromatography(SiO₂, Petroleum ether:Ethyl acetate=10:1-1:1) to give the productO1-tert-butyl O2-methyl (2R,4R)-4-fluoropyrrolidine-1,2-dicarboxylate(300 mg, 1.21 mmol, 94% yield) as yellow oil.

¹H NMR (400 MHz, Chloroform-d) δ 5.30-5.10 (m, 1H), 4.58-4.37 (m, 1H),3.94-3.76 (m, 1H), 3.75 (s, 3H), 3.72-3.55 (m, 1H), 2.54-2.23 (m, 2H),1.52-1.40 (m, 9H).

Step 2: [(2R,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methanol. To asolution of O1-tert-butyl O2-methyl(2R,4R)-4-fluoropyrrolidine-1,2-dicarboxylate. (300 mg, 1.21 mmol, 1.0eq) in THF (3.0 mL) was added LiAlH₄ (138 mg, 3.64 mmol, 3.0 eq) at −40°C. The mixture was stirred at this temperature for 1 hour, then heatedto 70° C. and stirred at 70° C. for 2 hours. After completion, thereaction mixture was quenched with saturated Na₂SO₄ aqueous (0.30 mL),then filtered. The mother liquor was collected and concentrated undervacuum to give the product[(2R,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methanol (130 mg, 976 umol,80% yield) as yellow oil.

¹H NMR (400 MHz, Chloroform-d) δ 5.18-4.98 (m, 1H), 3.76-3.70 (m, 1H),3.54-3.43 (m, 1H), 3.38-3.28 (m, 1H), 2.51-2.44 (m, 1H), 2.42-2.37 (m,1H), 2.35 (s, 3H), 2.34-2.26 (m, 1H), 2.21-2.09 (m, 1H).

Step A:benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2R,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of [(2R,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl] methanol(103 mg, 773 umol, 2.0 eq) and t-BuONa (55.8 mg, 580 umol, 1.50 eq) intoluene (2.0 mL) was added benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(230 mg, 387 umol, 1.0 eq). The mixture was stirred at 0° C. for 0.5hour. After completion, the reaction mixture was added water (10.0 mL)and extracted with ethyl acetate (10.0 ml×3). The organic layer wasdried over Na₂SO₄, filtered and concentrated. The residue was purifiedby reversed phase flash HPLC (C18, 0.1% FA in water, 0-60% MeCN) to givethe productbenzyl(2S)-2-(cyanomethyl)-4-[2-[[(2R,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(210 mg, 316 umol, 82% yield) as yellow solid. LCMS [ESI, M+1]:664.

¹H NMR (400 MHz, Chloroform-d) δ 7.70 (br d, J=8.4 Hz, 1H), 7.65 (t,J=8.6 Hz, 1H), 7.45-7.32 (m, 7H), 7.26-7.17 (m, 2H), 5.24-5.02 (m, 3H),4.73-4.61 (m, 1H), 4.53-4.42 (m, 1H), 4.30-4.18 (m, 2H), 4.11-3.96 (m,2H), 3.94-3.81 (m, 1H), 3.81-3.67 (m, 1H), 3.58-3.47 (m, 1H), 3.46-3.29(m, 2H), 3.24-3.06 (m, 3H), 3.05-2.96 (m, 1H), 2.92 (s, 3H), 2.82-2.71(m, 2H), 2.70-2.51 (m, 2H), 2.50-2.47 (m, 4H), 2.45-2.35 (m, 1H),2.12-2.05 (m, 1H).

Step B:2-[(2S)-4-[2-[[(2R,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2R,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 301 umol, 1.0 eq) and NH₃·MeOH (2.0 mL, 20% purity) in methanol(4.0 mL) was added Pd/C (80 mg, 10% purity). The mixture was purged byN₂ for 3 times, and then stirred under H₂ atmosphere (15 Psi) at 25° C.for 1 hour. After completion, the reaction mixture was filtered throughCelite. The mother liquor was concentrated under vacuum to give theproduct2-[(2S)-4-[2-[[(2R,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(140 mg, 264 umol, 88% yield) as yellow oil. The product was used forthe next step directly without further purification. LCMS [ESI,M+1]:664.

Step C:2-[(2S)-4-[2-[[(2R,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[2-[[(2R,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(120 mg, 226 umol, 1.0 eq), 2-fluoroprop-2-enoic acid (61.2 mg, 680umol, 3.0 eq) and DIEA (176 mg, 1.36 mmol, 238 uL, 6.0 eq) in DCM (3.0mL) was added HATU (258.44 mg, 679.69 umol, 3 eq). The mixture wasstirred at 0° C. for 0.5 hour. After completion, the reaction mixturewas added water (5.0 mL) and extracted with ethyl acetate (5.0 mL×3).The organic layer was dried over Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by prep-HPLC (column: Gemini 150*25 5u; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %:50%-80%, 12 min) to give the title compound2-[(2S)-4-[2-[[(2R,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile(EXAMPLE 518, 37.9 mg, 60.1 umol, 27% yield, 96% purity) as white solid.LCMS [ESI, M+1]: 602.

¹H NMR (400 MHz, Chloroform-d) δ 7.70 (br d, J=8.0 Hz, 1H), 7.65 (t,J=8.2 Hz, 1H), 7.45-7.37 (m, 1H), 7.34 (t, J=7.6 Hz, 1H), 7.27-7.18 (m,2H), 5.53-5.32 (m, 1H), 5.30-5.22 (m, 1H), 5.21-5.03 (m, 1H), 4.97-4.68(m, 1H), 4.52-4.42 (m, 1H), 4.29-4.20 (m, 2H), 4.18-4.03 (m, 2H),3.95-3.68 (m, 2H), 3.60-3.41 (m, 2H), 3.39-3.30 (m, 1H), 3.26-3.15 (m,2H), 3.15-2.95 (m, 2H), 2.92 (s, 3H), 2.90-2.54 (m, 4H), 2.53-2.46 (m,4H), 2.45-2.35 (m, 1H), 2.13-1.97 (m, 1H).

Example 519

2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[2-[[(2R,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

Step 1: O1-tert-butyl O2-methyl(2R,4R)-4-methoxypyrrolidine-1,2-dicarboxylate. To a solution ofO1-tert-butyl O2-methyl (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate(2.1 g, 8.56 mmol, 1 eq) in MeCN (42 mL) was added Ag₂O (5.95 g, 25.7mmol, 3 eq) and CH₃I (7.75 g, 54.6 mmol, 3.40 mL, 6.38 eq). The reactionmixture was stirred at 33° C. for 12 hours. The reaction mixture wasfiltered and the filtrate was concentrated under vacuum. The residue waspurified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=8/1 to 5/1) to give O1-tert-butyl O2-methyl(2R,4R)-4-methoxypyrrolidine-1,2-dicarboxylate (1.88 g, 6.89 mmol, 80%yield, 95.0% purity) as a colorless oil.

¹H NMR (400 MHz, chloroform-d) δ=4.45-4.26 (m, 1H), 3.96-3.89 (m, 1H),3.72 (s, 3H), 3.68-3.55 (m, 1H), 3.54-3.43 (m, 1H), 3.27 (s, 3H),2.38-2.17 (m, 2H), 1.51-1.37 (m, 9H).

Step 2: [(2R,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methanol. To thesolution of O1-tert-butyl O2-methyl(2R,4R)-4-methoxypyrrolidine-1,2-dicarboxylate (2.98 g, 11.5 mmol, 1 eq)in THF (60 mL) was added LiAlH₄ (872 mg, 23.0 mmol, 2 eq) at 0° C., themixture was stirred at 0° C. for 1 hour. Then the reaction mixture washeated to 80° C. and stirred for 2 hours. The mixture was quenched withsaturated Na₂SO₄ aqueous (3 mL), then filtered and the filter cake waswashed with THF (3×20 mL). The filtrate was concentrated under vacuum togive [(2R,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methanol (1.53 g, 10.0mmol, 87% yield, 95.0% purity) as a brown oil which was used for nextstep without further purification.

¹H NMR (400 MHz, chloroform-d) δ=3.82-3.76 (m, 1H), 3.69 (dd, J=3.2,11.2 Hz, 1H), 3.45 (dd, J=1.6, 10.8 Hz, 1H), 3.29 (s, 3H), 3.18 (d,J=10.4 Hz, 1H), 2.62 (br s, 1H), 2.42 (tdd, J=2.8, 6.4, 9.2 Hz, 1H),2.38-2.33 (m, 1H), 2.32 (s, 3H), 2.16 (ddd, J=6.8, 8.8, 14.0 Hz, 1H),1.92 (tdd, J=1.6, 6.8, 14.0 Hz, 1H).

Step A: (benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2R,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To the solution of [(2R,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methanol(1.37 g, 9.42 mmol, 2.8 eq) in toluene (40 mL) was added t-BuONa (970mg, 10.1 mmol, 3 eq) at 0° C., then benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(2 g, 3.36 mmol, 1 eq) was added at 0° C. the reaction mixture wasstirred at 0° C. for 0.5 hour. Water (20 mL) was added into the mixture.The mixture was diluted with EtOAc (10 mL) and extracted with EtOAc(2×20 mL). The combined organic layers were washed with brine (20 mL).The combined organic layers were dried over anhydrous Na₂SO₄, filteredand concentrated under vacuum. The residue was purified by reversedphase flash column (ACN/Water (0.1% FA)=57%) to give (benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2R,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1.8 g, 2.53 mmol, 75% yield, 95.0% purity)) as a yellow solid. LCMS[ESI, M+1]: 676.

¹H NMR (400 MHz, chloroform-d) δ=7.73-7.60 (m, 2H), 7.47-7.31 (m, 7H),7.27-7.16 (m, 2H), 5.21 (s, 2H), 4.67 (br s, 1H), 4.45 (br dd, J=4.4,10.0 Hz, 1H), 4.24-4.16 (m, 2H), 4.10-3.96 (m, 2H), 3.96-3.65 (m, 3H),3.59-3.40 (m, 2H), 3.29 (d, J=1.6 Hz, 3H), 3.25-3.06 (m, 4H), 3.00 (dt,J=3.6, 12.4 Hz, 1H), 2.91 (s, 3H), 2.81-2.55 (m, 4H), 2.45 (d, J=6.0 Hz,3H), 2.42-2.29 (m, 2H), 1.88-1.68 (m, 2H).

Step B:2-[(2S)-4-[2-[[(2R,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To the solution of benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2R,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(2 g, 2.96 mmol, 1 eq) and NH₃·MeOH (20 mL, 20% purity) in MeOH (40 mL)was added Pd/C (1 g, 10% purity) under N₂. The suspension was degassedunder vacuum and purged with H₂ several times. The mixture was stirredunder H₂ (15 psi) at 20° C. for 0.5 hour. The reaction mixture wasfiltered, the filtrate was concentrated under vacuum to give2-[(2S)-4-[2-[[(2R,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(1.29 g, 2.26 mmol, 76% yield, 95% purity) as a yellow solid which wasused for next step without further purification. LCMS [ESI, M+1]: 542.

Step C:2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[2-[[(2R,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To the solution of2-[(2S)-4-[2-[[(2R,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(150 mg, 277 umol, 1 eq), 2-fluoroprop-2-enoic acid (74.8 mg, 831 umol,3 eq) and TEA (336 mg, 1.66 mmol, 462 uL, 50% purity, 6 eq) in EtOAc (3mL) was added T3P (264 mg, 831 umol, 247 uL, 3 eq) at 0° C., the mixturewas stirred at 0° C. for 0.5 hour. Water (4 mL) was added into themixture. The mixture was extracted with EtOAc (3×8 mL). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by reversed phaseflash column (ACN/Water (0.1% FA)=32%). Then the residue was purified byprep-HPLC (column: Gemini 150*25 5 u; mobile phase: [water (0.05%ammonia hydroxide v/v)-ACN]; B %: 55%-85%, 12 min) to give titlecompound2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[2-[[(2R,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(EXAMPLE 519, 59.5 mg, 97.0 umol, 35% yield, 100% purity) as a whitesolid. LCMS [ESI, M+1]: 614.

¹H NMR (400 MHz, chloroform-d) δ=7.70 (br d, J=8.4 Hz, 1H), 7.65 (t,J=8.0 Hz, 1H), 7.45-7.38 (m, 1H), 7.34 (t, J=7.6 Hz, 1H), 7.27-7.17 (m,2H), 5.53-5.33 (m, 1H), 5.26 (dd, J=3.6, 16.8 Hz, 1H), 4.88 (br s, 1H),4.50-4.41 (m, 1H), 4.30-3.99 (m, 4H), 3.96-3.71 (m, 3H), 3.59-3.40 (m,2H), 3.30 (s, 3H), 3.25-3.15 (m, 3H), 3.14-2.94 (m, 2H), 2.92 (s, 3H),2.90-2.74 (m, 2H), 2.73-2.55 (m, 2H), 2.45 (d, J=5.6 Hz, 3H), 2.42-2.29(m, 2H), 1.81 (br dd, J=7.2, 14.4 Hz, 1H).

Example 520

2-[(2S)-4-[2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-(3-fluoroazetidin-1-yl)but-2-enoyl]piperazin-2-yl]acetonitrile

Step A:benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of [(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methanol(609.98 mg, 4.04 mmol, 3.0 eq) and t-BuONa (388 mg, 4.04 mmol, 3.0 eq)in toluene (2.0 mL) was dropwise added a solution ofbenzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(800 mg, 1.35 mmol, 1.0 eq) in toluene (4.0 mL) at 0° C. The reactionmixture was stirred at 0° C. for 0.5 hour. Ater completion, the reactionmixture was washed with water (15.0 mL) and extracted with ethyl acetate(3×20.0 mL). The Combine extracts were washed with brine (50.0 mL),dried with Na₂SO₄, filtrated and the solvent was removed under vacuum.The residue was purified by reversed phase flash HPLC [C18, 0.1% FA inwater, 0-80% MeCN]. The obtained product was then concentrated, theaqueous was extracted with Ethyl acetate (3×50.0 mL), the combinedorganic layer was dried over Na₂SO₄, filtered and concentrated. Compoundbenzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(750 mg, 1.08 mmol, 80.1% yield, 98%, purity) was obtained as yellowsolid. LCMS [ESI, M+1]: 682.

Step B:2-[(2S)-4-[2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(650 mg, 953 umol, 1.0 eq) and Pd/C (200 mg, 10% purity) was added inMeOH (8.0 mL) and NH₃·MeOH (8.0 mL, 20% purity) then the mixture wasdegassed and purged with H₂ for 3 times, and then the mixture wasstirred at 20° C. for 0.5 hour under H₂ (15 psi) atmosphere. Aftercompletion, the crude mixture was filtered through a pad of celite. Thecake was washed with MeOH (50.0 mL) and the filtrate dried under highvacuum. Compound2-[(2S)-4-[2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(420 mg, 736 umol, 77.2% yield, 96% purity) was obtained as yellowsolid. LCMS [ESI, M+1]: 548.

Step C:2-[(2S)-1-[(E)-4-bromobut-2-enoyl]-4-[2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(420 mg, 822 umol, 1.0 eq) and pyridine (520 mg, 6.57 mmol, 531 uL, 8.0eq) in DCM (6.0 mL) was added (E)-4-bromobut-2-enoyl chloride (603 mg,3.29 mmol, 4.0 eq). The mixture was stirred at 0° C. for 0.5 hour. Aftercompletion, the mixture was concentrated under vacuum. The product2-[(2S)-1-[(E)-4-bromobut-2-enoyl]-4-[2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(500 mg, crude) was obtained as yellow oil. The crude product was useddirectly to the next step without further purification LCMS [ESI, M+1]:695.

Step D: 2-[(2S)-4-[2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-(3-fluoroazetidin-1-yl)but-2-enoyl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-1-[(E)-4-bromobut-2-enoyl]-4-[2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(500 mg, 720 umol, 1.0 eq) and K₂CO₃ (995 mg, 7.20 mmol, 10.0 eq) inMeCN (12.0 mL) was added 3-fluoroazetidine (482 mg, 4.32 mmol, 6.0 eq,HCl) at 0° C. The mixture was stirred at 20° C. for 1 hour. Aftercompletion, the organic solvent was washed with water (10.0 mL). Theaqueous phase was extracted with ethyl acetate (3, 10 mL). Combineextracts were washed with brine (20.0 mL), dried with Na₂SO₄ the solventwas then removed under vacuum. The residue was purified by columnchromatography (Base Al₂O₃, Petroleum ether:Ethyl acetate=3:1 to Ethylacetate:Methanol=100.1), then the crude product was concentrated andpurified by prep-HPLC (column: Waters Xbridge 150×25 5 u; mobile phase:[water (0.05% ammonia hydroxide v/v)-ACN]; B %: 55%-79%, 10 min]; B %:45%-75%, 12 min) and lyophilization. Title compound2-[(2S)-4-[2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-(3-fluoroazetidin-1-yl)but-2-enoyl]piperazin-2-yl]acetonitrile(EXAMPLE 520, 45.8 mg, 66.5 umol, 9.24% yield, 100% purity) was obtainedas yellow solid. LCMS [ESI, M+1]: 689.

¹H NMR (400 MHz, chloroform-d) δ=7.74-7.63 (m, 2H), 7.47-7.32 (m, 2H),7.27-7.18 (m, 2H), 6.88 (br d, J=15.3 Hz, 1H), 6.42 (br d, J=15.4 Hz,1H), 5.27-5.05 (m, 1H), 4.64 (br s, 1H), 4.48-4.41 (m, 1H), 4.31-4.18(m, 2H), 4.16-3.95 (m, 2H), 3.94-3.84 (m, 1H), 3.82-3.66 (m, 3H), 3.54(br d, J=7.6 Hz, 1H), 3.50-3.36 (m, 2H), 3.34 (br d, J=3.8 Hz, 2H),3.30-3.24 (m, 1H), 3.24-3.08 (m, 4H), 3.07-2.95 (m, 2H), 2.92 (s, 3H),2.86-2.76 (m, 1H), 2.76-2.57 (m, 3H), 2.57-2.47 (m, 1H), 2.46 (d, J=4.5Hz, 3H), 2.34-2.17 (m, 1H).

Example 521

2-[(2S)-4-[7-(5,6-dimethyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile

Step A:2-[(2S)-4-[7-(5,6-dimethyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-2-(cyanomethyl)-4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(720 mg, 1.03 mmol, 1 eq) in DCM (1 mL) was added TFA (4.62 g, 40.5mmol, 3 mL, 39.4 eq). The mixture was stirred at 20° C. for 4 hours.Upon completion, the mixture was diluted with DCM (10 mL) andneutralized with saturated aqueous NaHCO₃. Then the aqueous phase wasextracted with EtOAc (2×30 mL). The combined organic layers were driedover Na₂SO₄ and concentrated under vacuum to give2-[(2S)-4-[7-(5,6-dimethyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(880 mg, crude) as a yellow solid which was used directly into the nextstep without further purification.

Step B:2-[(2S)-4-[7-(5,6-dimethyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(5,6-dimethyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(500 mg, crude), 2-fluoroprop-2-enoic acid (61.1 mg, 679 umol) and TEA(294 mg, 2.91 mmol, 405 uL) in DMF (10 mL) was added T3P (926 mg, 1.45mmol, 865 uL, 50% purity in EtOAc) at −40° C. Then the mixture wasstirred at −40° C. for 0.5 hour and 0° C. for another 0.5 hour. Uponcompletion, the mixture was diluted with water (20 mL) and extractedwith EtOAc (2×40 mL). The organic layers were washed with brine (50 mL),dried over Na₂SO₄ and concentrated under vacuum. The residue waspurified by reversed phase flash [water (0.1% FA)/acetonitrile]. Thedesired fractions were collected and neutralized with saturated aqueousNaHCO₃ and extracted with EtOAc (2×70 mL). The organic layers were driedover Na₂SO₄ and concentrated under vacuum. The residue was purified byprep-HPLC (column: Phenomenex Synergi C18 150*30 mm*4 um; mobile phase:[water (0.225% FA)-ACN]; B %: 10%-40%, 12 min). The desired fractionswere collected and lyophilized to give title compound2-[(2S)-4-[7-(5,6-dimethyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile(EXAMPLE 521, 52.5 mg, 79.8 umol, two steps 15% yield, 96.4% purity, FA)as a white solid. LCMS [ESI, M+1]:588.

SFC condition: Column: Chiralcel OJ-3 100×4.6 mm I.D., 3 um, Mobilephase: methanol (0.05% DEA) in CO₂ from 5% to 40%, Flow rate: 3 mL/min,Wavelength: 220 nm.

¹H NMR (400 MHz, chloroform-d) δ=8.03 (s, 1H), 7.15 (s, 1H), 5.53-5.34(m, 1H), 5.25 (br dd, J=3.2, 16.8 Hz, 1H), 5.02-4.61 (m, 3H), 4.43 (dd,J=4.8, 11.6 Hz, 1H), 4.27 (s, 2H), 4.19 (br d, J=13.2 Hz, 1H), 4.01 (brd, J=12.4 Hz, 1H), 3.68-3.56 (m, 1H), 3.55-3.50 (m, 2H), 3.49-3.21 (m,3H), 3.14 (br s, 1H), 2.98 (br s, 1H), 2.91-2.61 (m, 7H), 2.41 (s, 3H),2.34 (s, 3H), 2.23 (qd, J=8.4, 12.4 Hz, 1H), 2.14-1.95 (m, 3H).

Example 522

2-((S)-4-(2-(((2R,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4-hydroxybut-2-enoyl)piperazin-2-yl)acetonitrile

Step A:2-[(2S)-4-[2-[[(2R,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-trityloxybut-2-enoyl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[2-[[(2R,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(200 mg, 378 umol, 1.0 eq), (E)-4-trityloxybut-2-enoic acid (169 mg, 491umol, 1.3 eq) and DIEA (293 mg, 2.27 mmol, 395 uL, 6.0 eq) in DCM (3.0mL) was added HATU (431 mg, 1.13 mmol, 3.0 eq). The mixture was stirredat 0° C. for 0.5 hour. After completion, the mixture was added water (10mL) and extracted with ethyl acetate (2×10.0 mL). The organic layer wasdried over Na₂SO₄, filtered and concentrated. The residue was purifiedby column chromatography (SiO₂, Petroleum ether/Ethyl acetate=3/1 toEthyl acetate:Methanol=20:1). The product2-[(2S)-4-[2-[[(2R,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-trityloxybut-2-enoyl]piperazin-2-yl]acetonitrile(290 mg, 339 umol, 90% yield) was obtained as yellow solid.

Step B:2-[(2S)-4-[2-[[(2R,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-hydroxybut-2-enoyl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[2-[[(2R,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-trityloxybut-2-enoyl]piperazin-2-yl]acetonitrile(290 mg, 339 umol, 1.0 eq) in dichloromethane (1.5 mL) was added TFA(2.31 g, 20.3 mmol, 1.5 mL, 59.8 eq), the mixture was stirred at 20° C.for 0.5 hour. After completion, the reaction mixture was concentrated,then added dichlormethane (10.0 mL), the organic layer was washed withsaturated NaHCO₃ aqueous (2×10.0 mL), the organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was purified by columnchromatography (Base Al₂O₃, Petroleum ether/Ethyl acetate=3/1 to Ethylacetate:Methanol=20:1). The crude product was then repurfied byprep-HPLC (column: Gemini 150*25 5 u; mobile phase: [water (0.05%ammonia hydroxide v/v)-ACN]; B %: 45%-75%, 12 min), the obtained productwas concentrated and under lyophilization. Title compound2-[(2S)-4-[2-[[(2R,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-hydroxybut-2-enoyl]piperazin-2-yl]acetonitrile(EXAMPLE 522, 61.3 mg, 99.9 umol, 29% yield, 99% purity) was obtained aswhite solid. LCMS [ESI, M+1]: 614.

¹H NMR (400 MHz, chloroform-d) δ 7.73-7.61 (m, 2H), 7.46-7.31 (m, 2H),7.27-7.18 (m, 2H), 7.06 (br d, J=14.8 Hz, 1H), 6.62 (br d, J=14.8 Hz,1H), 5.27-4.97 (m, 1H), 4.74-4.55 (m, 1H), 4.52-4.34 (m, 3H), 4.31-4.16(m, 2H), 4.15-3.96 (m, 2H), 3.94-3.58 (m, 3H), 3.56-3.48 (m, 1H),3.46-3.41 (m, 1H), 3.36-3.29 (m, 1H), 3.26-3.07 (m, 3H), 3.04-2.97 (m,1H), 2.92 (s, 3H), 2.85-2.57 (m, 4H), 2.49 (d, J=4.8 Hz, 3H), 2.45-2.34(m, 1H), 2.29-1.91 (m, 2H).

Example 523

2-[(2S)-1-[(E)-4-hydroxybut-2-enoyl]-4-[2-[[(2R,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

Step A:2-[(2S)-4-[2-[[(2R,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-trityloxybut-2-enoyl]piperazin-2-yl]acetonitrile.To the solution of2-[(2S)-4-[2-[[(2R,4R)-4-methoxy-1-methyl-pyrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(200 mg, 369 umol, 1 eq), (E)-4-trityloxybut-2-enoic acid (254 mg, 738umol, 2 eq) and TEA (374 mg, 3.69 mmol, 514 uL, 10 eq) in EtOAc (4 mL)was added T3P (705 mg, 1.11 mmol, 659 uL, 50% purity, 3 eq) at 0° C.,the mixture was stirred at 0° C. for 0.5 hour. Water (10 mL) was addedinto the mixture. The mixture was diluted with EtOAc (5 mL) andextracted with EtOAc (15 mL). The organic layer was washed with brine(10 mL), dried over anhydrous Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by reversed phase flash column(ACN/Water (0.1% FA)=70%) to give2-[(2S)-4-[2-[[(2R,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-trityloxybut-2-enoyl]piperazin-2-yl]acetonitrile(230 mg, 262 umol, 71% yield, 99% purity) as a yellow solid.

Step B:2-[(2S)-1-[(E)-4-hydroxybut-2-enoyl]-4-[2-[[(2R,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To the solution of2-[(2S)-4-[2-[[(2R,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-trityloxybut-2-enoyl]piperazin-2-yl]acetonitrile(230 mg, 265 umol, 1 eq) in DCM (2.3 mL) was added TFA (3.54 g, 31.1mmol, 2.3 mL, 117 eq), the mixture was stirred at 15° C. for 1 hour. Thereaction mixture was basified with saturated NaHCO₃ (30 mL) to PH=7˜8,then extracted with DCM (2×15 mL). The combined organic layers weredried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. Theresidue was purified by reversed phase flash column (ACN/Water (0.1% FA)32%). Then the residue was purified by prep-HPLC (column: Gemini 150*255 u; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %:37%-67%, 12 min) to give title compound2-[(2S)-1-[(E)-4-hydroxybut-2-enoyl]-4-[2-[[(2R,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(EXAMPLE 523, 41.7 mg, 66.6 umol, 25% yield, 100% purity) as a whitesolid. LCMS [ESI, M+1]: 626.

¹H NMR (400 MHz, chloroform-d) δ=7.70 (br d, J=8.4 Hz, 1H), 7.65 (t,J=8.0 Hz, 1H), 7.45-7.38 (m, 1H), 7.37-7.31 (m, 1H), 7.27-7.17 (m, 2H),7.07 (br d, J=14.8 Hz, 1H), 6.62 (br d, J=14.0 Hz, 1H), 5.07 (br s, 1H),4.85-4.55 (m, 1H), 4.51-4.37 (m, 3H), 4.30-3.97 (m, 4H), 3.94-3.65 (m,2H), 3.58-3.40 (m, 2H), 3.29 (d, J=1.6 Hz, 3H), 3.25-2.96 (m, 5H), 2.92(s, 3H), 2.86-2.54 (m, 4H), 2.45 (d, J=4.8 Hz, 3H), 2.42-2.28 (m, 2H),1.81 (br dd, J=8.9, 13.6 Hz, 1H).

Example 524

2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4-methoxybut-2-enoyl)piperazin-2-yl)acetonitrile

Step A:2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4-methoxybut-2-enoyl)piperazin-2-yl)acetonitrile:A stirred mixture of2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(100 mg, 0.1879 mmol), (E)-4-methoxybut-2-enoic acid (32.73 mg, 0.2819mmol) and N,N-dimethylformamide (1 mL, 12.79 mmol) was cooled to 0° C.followed by addition of triethylamine (0.07859 mL, 0.5638 mmol) and2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide, 50% inEtOAc (0.1678 mL, 0.2819 mmol). The reaction mixture was stirred for 2hours while warming to room temperature. The mixture was partitionedbetween 0.5M Na₂CO₃ (5 mL) and EtOAc (15 mL) and the organics separated.The organics were next washed with water and brine (5 mL each), driedover Na₂SO₄ and evaporated in vacuo. The residue was nextchromatographed on silica gel using 4% MeOH+0.4% NH₄OH/DCM as eluent togive impure material which was further purified by Gilson reverse prepHPLC eluting with 5 to 75% ACN+0.1% TFA/H₂O+0.1% TFA. Fractionscontaining pure product were combined and partitioned between DCM and asaturated solution of Na₂CO₃ and the layers separated. The organics werenext washed with brine, dried over MgSO₄ and concentrated in vacuo togive pure title compound (EXAMPLE 524, 33 mg, 28%). ESI+APCI MS m/z630.3 [M⁺].

Example 525

N-(3-((S)-2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-3-oxoprop-1-en-2-yl)acetamide

Step A:N-(3-((S)-2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-3-oxoprop-1-en-2-yl)acetamide:To a 25 mL round bottom flask containing dichloromethane (2932 μl,0.2932 mmol) cooled to 0° C. was added2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(150 mg, 0.2932 mmol) and Hunig's base (307.2 μl, 1.759 mmol). Thereaction mixture was vigorously stirred while 2-Acetamidoacrylic acid(227.1 mg, 1.759 mmol) was added in one portion. Next,1-Propanephosphonic acid cyclic anhydride (1047 μl, 1.759 mmol) wasadded slowly to the stirring mixture. The reaction was stirred for 2hours at 0° C. The reaction was treated with basic water and the aqueouslayer extracted with EtOAc (3×). The combined organics were concentratedin vacuo and purified on the Gilson (prep HPLC) eluting with 5495% ACN0.1% TFA/water+0.1% TFA. Fractions containing product were combined andbasified with 1M NaOH and the aqueous layer extracted with DCM (2×). Theorganics were dried over Na₂SO₄ and concentrated in vacuo to give titlecompoundN-(3-((S)-2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-3-oxoprop-1-en-2-yl)acetamide(EXAMPLE 525, 124.2 mg, 68.03% yield). ESI+APCI MS m/z 623.3 [M+H]⁺.

Example 526

2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-3-(pyridin-4-yl)acryloyl)piperazin-2-yl)acetonitrile

2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-3-(pyridin-4-yl)acryloyl)piperazin-2-yl)acetonitrile:The title compound was prepared following Example 525 substitutingTrans-3-(4-Pyridyl) Acrylic Acid for 2-Acetamidoacrylic acid in Step A.ESI+APCI MS m/z 643.3 [M+H]⁺.

Example 527

2-((S)-1-(2-fluoroacryloyl)-(7-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

1-bromo-5-fluoro-3-methyl-2-(trifluoromethyl)benzene. To a solution of1-bromo-5-fluoro-2-iodo-3-methyl-benzene (2 g, 6.35 mmol, 1 eq) in DMF(40 mL) was added CuI (7.26 g, 38.1 mmol, 6 eq) and methyl2,2-difluoro-2-fluorosulfonyl-acetate (7.32 g, 38.1 mmol, 4.85 mL, 6eq). The mixture was stirred at 60° C. for 12 hours. The reactionmixture was diluted with ethyl acetate (20 mL) and washed with water (20mL×3). The organic layer was washed with brine (20 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=1/0 to 10/1).1-bromo-5-fluoro-3-methyl-2-(trifluoromethyl)benzene (1.3 g, 3.74 mmol,59% yield, 74% purity) was obtained as a yellow oil.

¹H NMR (400 MHz, chloroform-d) δ=7.33 (dd, J=2.4, 7.6 Hz, 1H), 6.95 (dd,J=2.0, 8.8 Hz, 1H), 2.54 (q, J=3.6 Hz, 3H).

2-bromo-6-fluoro-4-methyl-3-(trifluoromethyl)benzaldehyde. To a mixtureof 1-bromo-5-fluoro-3-methyl-2-(trifluoromethyl)benzene (900 mg, 3.50mmol, 1 eq) in THF (20 mL) was added LDA (2 M in THF, 3.50 mL, 2 eq) at−60° C. under nitrogen atmosphere. After stirring for 0.5 hour, to themixture was added DMF (768 mg, 10.5 mmol, 808 uL, 3 eq). The mixture wasstirred at −60° C. for 1 hour. The reaction was quenched with saturatedNH₄Cl aqueous solution (10 mL) and then extracted with ethyl acetate (50mL×3). The combined organic phase was washed with brine (10 mL), driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residuewas purified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=200/1 to 5/1).2-bromo-6-fluoro-4-methyl-3-(trifluoromethyl)benzaldehyde (700 mg, 2.46mmol, 70% yield) was obtained as a yellow oil.

¹H NMR (400 MHz, chloroform-d) δ=10.35 (s, 1H), 7.08 (d, J=10.4 Hz, 1H),2.66-2.58 (m, 3H).

4-bromo-6-methyl-5-(trifluoromethyl)-1H-indazole. A solution of2-bromo-6-fluoro-4-methyl-3-(trifluoromethyl)benzaldehyde (600 mg, 2.11mmol, 1 eq) and hydrazine monohydrate (2.11 g, 42.1 mmol, 2.05 mL, 20eq) in DMSO (8 mL) was stirred at 60° C. for 2 hours. The mixture wasdiluted with ethyl acetate (50 mL) and washed with water (3×50 mL) andbrine (1×50 mL). The separated organic layer was dried over sodiumsulfate, filtered and concentrated under vacuum. The residue was used tonext step without further purification.4-bromo-6-methyl-5-(trifluoromethyl)-1H-indazole (550 mg, 1.97 mmol, 94%yield) was obtained as a white solid.

4-bromo-6-methyl-1-tetrahydropyran-2-yl-5-(trifluoromethyl) indazole. Toa solution of 4-bromo-6-methyl-5-(trifluoromethyl)-1H-indazole (500 mg,1.79 mmol, 1 eq) in DCM (10 mL) was added 4-methylbenzenesulfonic acidhydrate (34.1 mg, 1791 umol, 0.1 eq) 1 followed by a solution of DHP(603 mg, 7.17 mmol, 655 uL, 4 eq) in CH₃CN (2 mL). The mixture wasstirred at 25° C. for 16 hours. The mixture was diluted with ethylacetate (100 mL) and washed with water (2×100 mL) and brine (1×50 mL).The organic layer was dried over sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by columnchromatography over silica gel (petroleum ether/ethyl acetate 20/1 to3/1). The desired fractions were collected and concentrated under vacuumto give 4-bromo-6-methyl-1-tetrahydropyran-2-yl-5-(trifluoromethyl)indazole (600 mg, 1.54 mmol, 86% yield, 93% purity) as a light yellowgum. LCMS [MSI, M+1]: 363.

Step A: tert-Butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[6-methyl-1-tetrahydropyran-2-yl-5-(trifluoromethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a mixture of tert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(400 mg, 848 umol, 1 eq),4-bromo-6-methyl-1-tetrahydropyran-2-yl-5-(trifluoromethyl) indazole(431 mg, 1.19 mmol, 1.4 eq) Pd₂(dba)₃ (155 mg, 170 umol, 0.2 eq), RuPhos(158 mg, 339 umol, 0.4 eq) and Cs₂CO₃ (691 mg, 2.12 mmol, 2.5 eq) intoluene (20 mL) was degassed and purged with N₂ for 3 times, and thenthe mixture was stirred at 100° C. for 16 hours under N₂ atmosphere. Tothe mixture was added H₂O (20 mL×1) and Ethyl acetate (20 mL×1). Theorganic phase was separated, filtered and concentrated under reducedpressure to give a residue. The residue was purified by silica gelchromatography (Ethyl acetate/Methanol=50/1 to 2/1). tert-Butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[6-methyl-1-tetrahydropyran-2-yl-5-(trifluoromethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 535 umol, 32% yield, 80.7% purity) was obtained as a yellowsolid. LCMS [MSI, M+1]: 754.

Step B:2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[6-methyl-1-tetrahydropyran-2-yl-5-(trifluoromethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(470 mg, 503 umol, 1 eq) in DCM (1 mL) was added TFA (2.29 g, 20.1 mmol,1.49 mL, 40 eq). The mixture was stirred at 25° C. for 1 h. To themixture was added dichloromethane (5 mL) and basified with saturatedaqueous NaHCO₃ solution to pH=8˜9. The organic phase was separated,dried over sodium sulfate, filtered and concentrated under reducedpressure to give2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(420 mg, 453 umol, 90% yield, 61.4% purity) was obtained as a yellowsolid and used into next step without further purification. LCMS [MSI,M+1]: 570.

Step C:2-((S)-1-(2-fluoroacryloyl)-4-(7-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.To a solution of 2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(380 mg, 410 umol, 1 eq), 2-fluoroprop-2-enoic acid (18.4 mg, 205 umol,0.5 eq) and TEA (124 mg, 1.23 mmol, 171 uL, 3 eq) in DMF (8 mL) wasadded T3P (391 mg, 614 umol, 365 uL, 50% purity in DMF, 1.5 eq) at −40°C. Then the mixture was stirred at −40° C. for 0.5 hour and 0° C. foranother 0.5 hour. 2-fluoroprop-2-enoic acid (11 mg) and T3P (100 uL) wasadded and the mixture was stirred at −40° C. for further 0.5 hour. Themixture was diluted with water (15 mL) and extracted with EtOAc (2×40mL). The organic layers were washed with brine (50 mL), dried overNa₂SO₄ and concentrated under vacuum. The residue was purified byprep-HPLC (column: Luna C18 150*25 5 u; mobile phase: [water (0.225%FA)-ACN]; B %: 22%-42%, 7.8 min) and (column: Phenomenex Gemini 150*25mm*10 um; mobile phase: [water (0.04% NH₃·H₂O+10 mM NH₄HCO₃)-ACN]; B %:50%-68%, 12 min). The desired fractions were collected and lyophilize togive title compound2-((S)-1-(2-fluoroacryloyl)-4-(7-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(EXAMPLE 527) as white solid.

Example 528

2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4-(3-fluoroazetidin-1-yl)but-2-enoyl)piperazin-2-yl)acetonitrile

The title compound is prepared following Example 520 by modifyingIntermediate 66 by substituting(S)-(4,4-difluoro-1-methylpyrrolidin-2-yl)methanol for(1-methylpyrrolidin-2-yl)methanol in Intermediate 66, Step E, modifiedIntermediate 66 is deprotected using the conditions in Intermediate 71,Step A, then substituted for Intermediate 66 in Example 520, Step A.

Example 529

2-((S)-4-(2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4-fluorobut-2-enoyl)piperazin-2-yl)acetonitrile

The title compound was prepared following Example 467 substituting(E)-4-fluorobut-2-enoic acid for acryloyl chloride using the conditionsof Example 479, Step C. LCMS [ESI, M+1]: 634.

¹H NMR (400 MHz, chloroform-d) δ=7.70 (br d, J=8.0 Hz, 1H), 7.66 (t,J=8.0 Hz, 1H), 7.45-7.38 (m, 1H), 7.38-7.32 (m, 1H), 7.27-7.18 (m, 2H),7.09-6.93 (m, 1H), 6.60 (br d, J=14.8 Hz, 1H), 5.32-4.93 (m, 3H), 4.64(br s, 1H), 4.45 (td, J=5.2, 11.2 Hz, 1H), 4.32-3.63 (m, 6H), 3.58-3.36(m, 3H), 3.25-2.96 (m, 5H), 2.93 (s, 3H), 2.88-2.77 (m, 1H), 2.75-2.50(m, 3H), 2.46 (d, J=4.4 Hz, 3H), 2.34-2.15 (m, 1H).

SFC condition: Column: Chiralcel OJ-3 50×4.6 mm I.D., 3 um, Mobilephase: methanol (0.05% DEA) in CO₂ from 5% to 40%, Flow rate: 3 mL/min,Wavelength: 220 nm.

Example 530

2-((S)-4-(2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

The title compound was prepared following Example 467 substituting2-fluoroprop-2-enoyl chloride for acryloyl chloride using the conditionsof Example 478, Step A. LCMS [ESI, M+1]:620.

¹H NMR (400 MHz, chloroform-d) δ=7.73-7.63 (m, 2H), 7.46-7.33 (m, 2H),7.27-7.18 (m, 2H), 5.54-5.33 (d, J=47.6 Hz, 1H), 5.26 (dd, J=3.6, 16.8Hz, 1H), 5.05-4.62 (m, 1H), 4.58-4.37 (m, 1H), 4.31-4.13 (m, 3H),4.12-4.05 (m, 1H), 3.97-3.73 (m, 1H), 3.59-3.36 (m, 3H), 3.27-2.95 (m,6H), 2.92 (s, 3H), 2.89-2.49 (m, 5H), 2.46 (d, J=4.4 Hz, 3H), 2.34-2.17(m, 1H).

SFC: “Column: Chiralcel OJ-3 50×4.6 mm I.D., 3 um Mobile phase: methanol(0.05% DEA) in CO₂ from 5% to 40% Flow rate: 3 mL/min Wavelength. 220nm”.

Example 531

2-((S)-4-(2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4-methoxybut-2-enoyl)piperazin-2-yl)acetonitrile

The title compound is prepared following Example 467 substituting(methoxymethyl)prop-2-enoic acid for acryloyl chloride using theconditions of Example 489, Step A.

Example 532

2-((S)-4-(2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4-hydroxybut-2-enoyl)piperazin-2-yl)acetonitrile

The title compound is prepared following Example 467 substituting4-[tert-butyl(dimethyl)silyl]oxybut-2-ynoic acid for acryloyl chlorideusing the conditions of Example 483, Step A.

Example 533

(S,E)-1-(4-(2-((4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6-dimethyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-4-fluorobut-2-en-1-one

The title compound is prepared following Example 469 substituting(E)-4-fluorobut-2-enoic acid for prop-2-enoyl prop-2-enoate in Example479, Step C.

Example 534

(S,E)-1-(4-(2-((4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6-dimethyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-4-methoxybut-2-en-1-one

The title compound is prepared following Example 469 substituting2-(methoxymethyl)prop-2-enoic acid for prop-2-enoyl prop-2-enoate inExample 489, Step A.

Example 535

(S)-1-(4-(2-((4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6-dimethyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoroprop-2-en-1-one

The title compound is prepared following Example 469 substituting2-fluoroacrylic acid for prop-2-enoyl prop-2-enoate in Example 478, StepA.

Example 536

(S,E)-1-(4-(2-((4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6-dimethyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-4-hydroxybut-2-en-1-one

The title compound is prepared following Example 469 substituting4-[tert-butyl(dimethyl)silyl]oxybut-2-ynoic acid for prop-2-enoylprop-2-enoate in Example 469, Step D, and following the procedures ofExample 483, Step A.

Example 537

(S)-1-(4-(2-((4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6-dimethyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoroprop-2-en-1-one

The title compound is prepared following Example 470 substituting(E)-4-fluorobut-2-enoic acid for prop-2-enoyl prop-2-enoate in Example478, Step A.

Example 538

(S,E)-1-(4-(2-((4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6-dimethyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-4-fluorobut-2-en-1-one

The title compound is prepared following Example 470 substituting(E)-4-fluorobut-2-enoic acid for prop-2-enoyl prop-2-enoate in Example479, Step C.

Example 539

(S)-1-(4-(2-((4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6-dimethyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoroprop-2-en-1-one

The title compound is prepared following Example 470 substituting2-fluoroacrylic acid for prop-2-enoyl prop-2-enoate in Example 478, StepA.

Example 540

(S,E)-1-(4-(2-((4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6-dimethyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-4-methoxybut-2-en-1-one

The title compound is prepared following Example 470 substituting2-(methoxymethyl)prop-2-enoic acid for prop-2-enoyl prop-2-enoate inExample 489, Step A.

Example 541

(S,E)-1-(4-(2-((4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6-dimethyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-4-hydroxybut-2-en-1-one

The title compound is prepared following Example 470 substituting4-[tert-butyl(dimethyl)silyl]oxybut-2-ynoic acid for prop-2-enoylprop-2-enoate in Example 470, Step C and following the procedures ofExample 483. Step A.

Example 542

2-((S)-4-(2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4-fluorobut-2-enoyl)piperazin-2-yl)acetonitrile

The title compound was prepared following Example 468 substituting2-fluoroprop-2-enoyl chloride for acryloyl chloride using the conditionsof Example 479, Step C. LCMS [ESI, M+1]: 655.

¹H NMR (400 MHz, Chloroform-d) δ=7.76 (d, J=8.0 Hz, 1H), 7.63 (t, J=7.2Hz, 1H), 7.53 (d, J=7.2 Hz, 1H), 7.50-7.40 (m, 1H), 7.34 (t, J=7.8 Hz,1H), 7.26-7.18 (m, 1H), 7.08-6.94 (m, 1H), 6.60 (br d, J=14.8 Hz, 1H),5.26-5.03 (m, 2H), 4.90-4.58 (m, 1H), 4.52-4.38 (m, 2H), 4.31-4.21 (m,1H), 4.19-3.98 (m, 2H), 3.97-3.72 (m, 2H), 3.66-7.56 (m, 1H), 3.53-3.37(m, 2H), 3.34-3.11 (m, 3H), 3.07-2.92 (m, 2H), 2.89-2.79 (m, 1H),2.77-2.48 (m, 4H), 2.47 (d, J=2.4 Hz, 3H), 2.35-2.18 (m, 1H).

Example 543

2-((S)-4-(2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

The title compound was prepared following Example 468 substituting2-fluoroprop-2-enoyl chloride for acryloyl chloride using the conditionsof Example 478, Step A. LCMS [ESI, M+1]: 640.

¹H NMR (400 MHz, chloroform-d) δ=7.76 (d, J=8.0 Hz, 1H), 7.63 (t, J=7.2Hz, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.45 (td, J=7.6, 12.4 Hz, 1H), 7.34 (t,J=7.6 Hz, 1H), 7.27-7.19 (m, 1H), 5.54-5.33 (dd, J=2.8, 47.6 Hz, 1H),5.26 (dd, J=3.6, 16.8 Hz, 1H), 4.85 (br s, 1H), 4.51-4.38 (m, 2H),4.31-3.77 (m, 4H), 3.69-3.54 (m, 1H), 3.41 (m, 2H), 3.35-2.48 (m, 1H),2.47 (d, J=2.4 Hz, 3H), 2.35-2.16 (m, 1H).

SFC: “Column: Cellucoat 50×4.6 mm I.D., 3 um Mobile phase: methanol(0.05% DEA) in CO₂ from 5% to 40% Flow rate: 3 mL/min Wavelength: 220nm”.

Example 544

2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4-methoxybut-2-enoyl)piperazin-2-yl)acetonitrile

The title compound is prepared following Example 468 substituting(methoxymethyl)prop-2-enoic acid for acryloyl chloride using theconditions of Example 489, Step A.

Example 545

2-((S)-4-(2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(8-chloronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4-hydroxybut-2-enoyl)piperazin-2-yl)acetonitrile

The title compound is prepared following Example 468 substituting4-[tert-butyl(dimethyl)silyl]oxybut-2-ynoic acid for acryloyl chlorideusing the conditions of Example 483, Step A.

Example 546

2-((S)-4-(2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4-fluorobut-2-enoyl)piperazin-2-yl)acetonitrile

The title compound is prepared following Example 527 substituting2-fluoroprop-2-enoyl chloride for acryloyl chloride using the conditionsof Example 479, Step C.

Example 547

2-((S)-4-(2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

The title compound is prepared following Example 527 substituting2-fluoroprop-2-enoyl chloride for acryloyl chloride using the conditionsof Example 478, Step A.

Example 548

2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4-methoxybut-2-enoyl)piperazin-2-yl)acetonitrile

The title compound is prepared following Example 527 substituting(methoxymethyl)prop-2-enoic acid for acryloyl chloride using theconditions of Example 489, Step A.

Example 549

2-((S)-4-(2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(8-chloronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4-hydroxybut-2-enoyl)piperazin-2-yl)acetonitrile

The title compound is prepared following Example 527 substituting4-[tert-butyl(dimethyl)silyl]oxybut-2-ynoic acid for acryloyl chlorideusing the conditions of Example 483, Step A.

Example 550

2-((S)-4-(7-(5,6-dimethyl-1H-indol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

2-((S)-1-acryloyl-4-(7-(5,6-dimethyl-1H-indol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.The title compound is prepared following Example 466 substituting2-fluoroacrylic acid for prop-2-enoyl prop-2-enoate as described inExample 478, Step A.

Example 551

2-[(2S)-4-[2-[[(2R,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-methoxybut-2-enoyl]piperazin-2-yl]acetonitrile

Step A:2-[(2S)-4-[2-[[(2R,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-methoxybut-2-enoyl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[2-[[(2R,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(200 mg, 378 umol, 1.0 eq), (E)-4-methoxybut-2-enoic acid (110 mg, 944umol, 2.5 eq) in DMF (3.0 mL) was added TEA (382 mg, 3.78 mmol, 526 uL,10.0 eq) and T3P (721 mg, 1.13 mmol, 674 uL, 50% purity, 3.0 eq). Themixture was stirred at 0° C. for 0.5 hour. After completion, the organicsolvent was washed with water (10.0 mL). The aqueous phase was extractedwith ethyl acetate (3×10.0 mL). Combine extracts were washed with brine(20.0 mL), dried with Na₂SO₄ and filtrated. The solvent was then removedunder vacuum. The residue was purified by column chromatography (BaseAl₂O₃, Petroleum ether:Ethyl acetate=10:1 to 1:1), then the crudeproduct was concentrated and repurified by prep-HPLC (column: PhenomenexGemini 150×25 mm×10 um; mobile phase: [water (0.05% ammonia hydroxidev/v)-ACN]; B %: 48%-78%, 9-10 min) and lyophilization to give titlecompound2-[(2S)-4-[2-[[(2R,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-methoxybut-2-enoyl]piperazin-2-yl]acetonitrile(EXAMPLE 551, 50 mg, 79.6 umol, 21% yield, 99.9% purity) was obtained asyellow solid. LCMS [ESI, M+1]: 628.

¹H NMR (400 MHz, Chloroform-d) δ=7.73-7.62 (m, 2H), 7.45-7.31 (m, 2H),7.27-7.18 (m, 2H), 7.05-6.94 (m, 1H), 6.55 (br d, J=15.0 Hz, 1H),5.23-5.03 (m, 1H), 4.66 (br s, 1H), 4.52-4.42 (m, 1H), 4.30-4.18 (m,2H), 4.18-3.94 (m, 4H), 3.93-3.84 (m, 1H), 3.83-3.65 (m, 1H), 3.54 (brd, J=6.7 Hz, 1H), 3.44 (s, 3H), 3.42-3.26 (m, 2H), 3.25-3.15 (m, 2H),3.05 (br dd, J=8.5, 16.4 Hz, 2H), 2.92 (s, 3H), 2.88-2.58 (m, 4H),2.57-2.35 (m, 5H), 2.14-1.96 (m, 1H).

Example 552

2-[(2S)-1-[(E)-4-methoxybut-2-enoyl]-4-[2-[[(2R,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

Step A:2-[(2S)-1-[(E)-4-methoxybut-2-enoyl]-4-[2-[[(2R,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To the solution of2-[(2S)-4-[2-[[(2R,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(150 mg, 277 umol, 1 eq), (E)-4-methoxybut-2-enoic acid (64.3 mg, 554umol, 2 eq) and TEA (280 mg, 2.77 mmol, 385 uL, 10 eq) in DMF (3 mL) wasadded T3P (529 mg, 831 umol, 494 uL, 50% purity, 3 eq) at 0° C., themixture was stirred at 0° C. for 0.5 hour. Water (10 mL) was added intothe mixture. The mixture was diluted with EtOAc (5 mL) and extractedwith EtOAc (2×10 mL). The combined organic layers were washed with brine(10 mL), dried over anhydrous Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by reversed phase flash column(ACN/Water (0.1% FA)=35%). Then the residue was purified by prep-HPLC(column: Waters Xbridge 150*25 5 u; mobile phase: [water (0.05% ammoniahydroxide v/v)-ACN]; B %: 50%-74%, 10 min) to give title compound2-[(2S)-1-[(E)-4-methoxybut-2-enoyl]-4-[2-[[(2R,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(EXAMPLE 552, 37.1 mg, 57.2 umol, 21% yield, 98.7% purity) as a whitesolid. LCMS [ESI, M+1]: 640.

¹H NMR (400 MHz, chloroform-d) δ=7.72-7.61 (m, 2H), 7.45-7.31 (m, 2H),7.27-7.17 (m, 2H), 6.99 (br d, J=14.8 Hz, 1H), 6.55 (br d, J=15.2 Hz,1H), 5.07 (br s, 1H), 4.51-4.40 (m, 1H), 4.31-4.04 (m, 5H), 3.95-3.68(m, 3H), 3.63-3.47 (m, 2H), 3.44 (s, 3H), 3.42-3.35 (m, 1H), 3.30 (d,J=1.2 Hz, 3H), 3.24-2.96 (m, 5H), 2.92 (s, 3H), 2.76 (br dd, J=8.0, 16.8Hz, 1H), 2.72-2.52 (m, 3H), 2.45 (d, J=5.2 Hz, 3H), 2.41-2.27 (m, 2H),1.81 (br dd, J=7.2, 14.0 Hz, 1H).

Example 553

2-((S)-1-((E)-4-methoxybut-2-enoyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((R)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: methyl 3-hydroxy-4-methoxy-butanoate. To a solution of methyl4-methoxy-3-oxo-butanoate (20 g, 137 mmol, 1.0 eq) in toluene (300 mL)was added NaBH₄ (5.44 g, 144 mmol, 1.05 aq) at 0° C. Then the mixturewas stirred at 20° C. for 4 hours. After completion, the mixture wasdiluted with water (100 mL) at 0° C. and extracted with ethyl acetate(3×1.00 mL). The extracts were washed with brine (200 mL), dried overNa₂SO₄, filtered and concentrated under vacuum to give methyl3-hydroxy-4-methoxy-butanoate (7.5 g, crude) as yellow oil and used intonext step without further purification.

¹H NMR (400 MHz, chloroform-d) δ=4.23-4.15 (m, 1H), 3.70 (s, 3H),3.44-3.38 (m, 2H), 3.37 (s, 3H), 3.04 (br s, 1H), 2.51 (d, J=6.4 Hz,2H).

Step B: methyl (E)-4-methoxybut-2-enoate. To a solution of methyl3-hydroxy-4-methoxy-butanoate (7.5 g, crude) in DCM (50.0 mL) was addedTEA (5.12 g, 50.6 mmol, 7.05 mL) and MsCl (8.70 g, 75.9 mmol, 5.88 mL)at 0° C. After stirred for 4 hours, to the mixture was added TEA (10.2g, 101 mmol, 14.1 mL) 0° C. The mixture was warmed up to 20° C. andstirred for 12 hours. After completion, the mixture was diluted withwater (50.0 mL), washed with HCl (1N, 15.0 mL) and brine (20.0 mL),dried over Na₂SO₄, filtered and concentrated under vacuum. The residuewas purified by column chromatography (SiO₂. Petroleum ether/Ethylacetate=1/0 to 50:1) to give methyl (E)-4-methoxybut-2-enoate (1.7 g,11.8 mmol, two steps 8.6% yield, 90% purity) as yellow oil.

¹H NMR (400 MHz, chloroform-d) δ=6.93 (td, J=4.3, 15.8 Hz, 1H), 6.04(td, J=2.0, 15.8 Hz, 1H), 4.06 (dd, J=2.0, 4.3 Hz, 2H), 3.72 (s, 3H),3.36 (s, 3H).

Step C: (E)-4-methoxybut-2-enoic acid. A mixture of methyl(E)-4-methoxybut-2-enoate (300 mg, 2.31 mmol, 1.0 eq) and KOH (517 mg,9.22 mmol, 4.0 eq) in MeOH (2.0 mL) and H₂O (2.0 mL) was stirred at 20°C. for 2 hours. After completion, the mixture was acidified with HCl(2N, 5.0 mL) to pH=1-3 and extracted with ethyl acetate (2×20 mL). Theorganic layers were dried over Na₂SO₄, filtered and concentrated undervacuum to give (E)-4-methoxybut-2-enoic acid (200 mg, 1.55 mmol, 67.3%yield, 90% purity) as yellow solid.

¹H NMR (400 MHz, chloroform-d) δ=11.13 (br s, 1H), 7.06 (td, J=4.1, 15.7Hz, 1H), 6.08 (td, J=2.0, 15.7 Hz, 1H), 4.12 (dd, J=2.0, 4.1 Hz, 2H),3.40 (s, 3H).

Step D:2-[(2S)-1-[(E)-4-methoxybut-2-enoyl]-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(200 mg, 391 umol, 1 eq), (E)-4-methoxybut-2-enoic acid (113 mg, 977umol, 2.5 eq), TEA (395 mg, 3.91 mmol, 544 uL, 10 eq) in DMF (4 mL) wasadded T3P (746 mg, 1.17 mmol, 697 uL, 50% purity, 3 eq) at 0° C. Themixture was stirred at 0° C. for 0.3 hour. The reaction mixture wasdiluted with ethyl acetate (20 mL) and washed with water (10 mL×3). Theorganic layers were washed with brine (10 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by column chromatography (SiO₂, Ethylacetate/MeOH=100/1 to 10:1) and further purified by prep-HPLC (column:Boston pH-1 ex 150*25 10 um; mobile phase: [water (0.1% TFA)-ACN], B %:35%-59%, 8 min). The mixture was collected and lyophilized. Titlecompound2-[(2S)-1-[(E)-4-methoxybut-2-enoyl]-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(EXAMPLE 553, 37.5 mg, 60.4 umol, 15% yield, 98.2% purity) was obtainedas a white solid. LCMS [ESI, M+1]: 610.

¹H NMR (400 MHz, chloroform-d) δ=7.77-7.57 (m, 2H), 7.46-7.37 (m, 1H),7.34 (t, J=7.6 Hz, 1H), 7.27-7.17 (m, 2H), 6.99 (br d, J=14.4 Hz, 1H),6.55 (br d, J=14.8 Hz, 1H), 5.24-4.49 (m, 1H), 4.46-4.32 (m, 1H),4.32-3.74 (m, 7H), 3.73-3.25 (m, 6H), 3.25-2.94 (m, 5H), 2.92 (s, 3H),2.86-2.54 (m, 4H), 2.49 (d, J=5.6 Hz, 3H), 2.38-2.23 (m, 1H), 2.11-2.00(m, 1H), 1.93-1.65 (m, 3H).

Example 554

2-[(2S)-1-[(E)-4-Methoxybut-2-enoyl]-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

Step A: tert-butyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.A mixture oftert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(850 mg, 1.80 mmol, 1.0 eq), 1-bromo-8-methyl-naphthalene (1.20 g, 5.41mmol, 3.0 eq), Pd₂(dba)₃ (330 mg, 360 μmol, 0.20 eq), Xantphos (417 mg,721 μmol. 0.40 eq) and Cs₂CO₃ (1.76 g, 5.41 mmol, 3.0 eq) in toluene(10.0 mL) was degassed and purged with N₂ for 3 times, and then themixture was stirred at 90° C. for 8 hours under N₂. After completion,the reaction was washed with 2 N HCl (2×15.0 mL). The aqueous phase wasbasified with solid NaHCO₃ to pH˜7 and extracted with ethyl acetate(2×50.0 mL). The organic layers were dried over Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by reverse phaseflash HPLC [C18, 0.1% FA in water, 0-65% MeCN] and was adjusted withsolid NaHCO₃ to pH˜7 and extracted with ethyl acetate (2×150 mL). Theorganic layers were dried over Na₂SO₄, filtered and concentrated undervacuum. Compound tert-butyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(650 mg, 1.03 mmol, 57% yield, 97% purity) was obtained as white solid.LCMS [ESI, M+1]: 612.

¹H NMR (400 MHz, chloroform-d) δ 7.72-7.61 (m, 2H), 7.44-7.37 (m, 1H),7.36-7.30 (m, 1H), 7.27-7.16 (m, 2H), 4.63-4.52 (m, 1H), 4.46-4.36 (m,1H), 4.30-4.15 (m, 2H), 4.09-3.95 (m, 2H), 3.93-3.73 (m, 2H), 3.57-3.47(m, 1H), 3.42-3.27 (m, 1H), 3.22-3.04 (m, 4H), 3.02-2.94 (m, 1H), 2.92(s, 3H), 2.81-2.54 (m, 4H), 2.53-2.47 (m, 3H), 2.40-2.26 (m, 1H),2.12-2.05 (m, 1H), 1.92-1.71 (m, 3H), 1.52 (s, 9H).

Step B:2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(600 mg, 981 μmol, 1.0 eq) in dioxane (3.0 mL) was added HCl/dioxane (4M, 3.0 mL, 12.2 eq) at 25° C., and the mixture was stirred at 25° C. for1 hour. After completion, the reaction mixture was quenched by saturatedaqueous NaHCO₃ (8.0 mL) at 0° C., and then diluted with H₂O (5.0 mL) andextracted with ethyl acetate (3×15.0 mL). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated under reduced pressureto give2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(410 mg, crude) as yellow solid which was used into the next stepwithout further purification.

Step C:2-[(2S)-1-[(E)-4-methoxybut-2-enoyl]-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile. To a solution of2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(150 mg, 293 μmol, 1.0 eq), (E)-4-methoxybut-2-enoic acid (102 mg, 880μmol, 3.0 eq) in ethyl acetate (3.0 mL) was added TEA (237 mg, 2.35mmol, 326 μL, 8.0 eq) and T3P (560 mg, 880 μmol, 523 μL, 50% purity, 3.0eq) at 0° C. The mixture was stirred at 20° C. for 1 hour. Aftercompletion, water was added (5.0 mL). The organic layer was separated,and the aqueous phase was extracted with ethyl acetate (3×10 mL).Combined extracts were washed with brine (20.0 mL), dried with Na₂SO₄,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography (basic Al₂O₃, petroleum ether:ethyl acetate=3:1 toethyl acetate:methanol=50:1), then the crude product repurified byprep-HPLC (column: Waters Xbridge 150*25 5 u; mobile phase: [water(0.05% ammonium hydroxide v/v)-MeCN]; B %: 50%-77%, 10 min) andlyophilization. Compound2-[(2S)-1-[(E)-4-methoxybut-2-enoyl]-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile (38.6 mg, 62.4 μmol, 21% yield, 98% purity) was obtained aswhite solid. LCMS [ESI, M+1]: 512.

Step D:2-[(2S)-1-[(E)-4-methoxybut-2-enoyl]-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile. To a solution of2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(150 mg, 293 μmol, 1.0 eq), (E)-4-methoxybut-2-enoic acid (102 mg, 880μmol, 3.0 eq) in ethyl acetate (3.0 mL) was added TEA (237 mg, 2.35mmol, 326 μL, 8.0 eq) and T3P (560 mg, 880 μmol, 523 μL, 50% purity, 3.0eq) at 0° C. The mixture was stirred at 20° C. for 1 hour. Aftercompletion, water was added (5.0 mL). The organic layer was separated,and the aqueous phase was extracted with ethyl acetate (3×10 mL).Combined extracts were washed with brine (20.0 mL), dried with Na₂SO₄,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography (basic Al₂O₃, petroleum ether:ethyl acetate=3:1 toethyl acetate:methanol=50:1), then the crude product repurified byprep-HPLC (column: Waters Xbridge 150*25 5 u; mobile phase: [water(0.05% ammonium hydroxide v/v)-MeCN]; B %: 50%-77%, 10 min) andlyophilization. Compound2-[(2S)-1-[(E)-4-methoxybut-2-enoyl]-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile (38.6 mg, 62.4 μmol, 21% yield, 98% purity) was obtained aswhite solid. LCMS [ESI, M+1]: 610.

¹H NMR (400 MHz, chloroform-d) δ 7.73-7.62 (m, 2H), 7.45-7.31 (m, 2H),7.26-7.17 (m, 2H), 6.99 (br d, J=15.2 Hz, 1H), 6.55 (br d, J=15.6 Hz,1H), 5.20-4.50 (m, 1H), 4.43-4.33 (m, 1H), 4.29-3.96 (m, 6H), 3.94-3.83(m, 1H), 3.81-3.63 (m, 1H), 3.58-3.37 (m, 5H), 3.23-2.96 (m, 5H), 2.92(s, 3H), 2.87-2.54 (m, 4H), 2.52-2.43 (m, 3H), 2.33-2.24 (m, 1H),2.13-2.01 (m, 1H), 1.87-1.72 (m, 3H).

Example 555

2-((S)-1-(2-Fluoroacryloyl)-4-(7-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

1-Bromo-5-fluoro-3-methyl-2-(trifluoromethyl)benzene. To a solution of1-bromo-5-fluoro-2-iodo-3-methyl-benzene (2 g, 6.35 mmol, 1 eq) in DMF(40 mL) was added CuI (7.26 g, 38.1 mmol, 6 eq) and methyl2,2-difluoro-2-fluorosulfonyl-acetate (7.32 g, 38.1 mmol, 4.85 mL, 6eq). The mixture was stirred at 60° C. for 12 hours. The reactionmixture was diluted with ethyl acetate (20 mL) and washed with water (20mL×3). The organic layer was washed with brine (20 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (SiO₂,petroleum ether/ethyl acetate 1/0 to 10/1).1-bromo-5-fluoro-3-methyl-2-(trifluoromethyl)benzene (1.3 g, 3.74 mmol,59% yield, 74% purity) was obtained as a yellow oil.

¹H NMR (400 MHz, chloroform-d) δ=7.33 (dd, J=2.4, 7.6 Hz, 1H), 6.95 (dd,J=2.0, 8.8 Hz, 1H), 2.54 (q, J=3.6 Hz, 3H).

2-Bromo-6-fluoro-4-methyl-3-(trifluoromethyl)benzaldehyde. To a mixtureof 1-bromo-5-fluoro-3-methyl-2-(trifluoromethyl)benzene (900 mg, 3.50mmol, 1 eq) in THF (20 mL) was added LDA (2 M in THF, 3.50 mL, 2 eq) at−60° C. under nitrogen. After stirring for 0.5 hour, to the mixture wasadded DMF (768 mg, 10.5 mmol, 808 μL, 3 eq). The mixture was stirred at−60° C. for 1 hour. The reaction was quenched with saturated aqueousNH₄Cl (10 mL) and then extracted with ethyl acetate (50 mL×3). Thecombined organic phase was washed with brine (1×10 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by column chromatography (SiO₂, petroleum ether/ethylacetate=200/1 to 5/1).2-bromo-6-fluoro-4-methyl-3-(trifluoromethyl)benzaldehyde (700 mg, 2.46mmol, 70% yield) was obtained as a yellow oil.

¹H NMR (400 MHz, chloroform-d) δ=10.35 (s, 1H), 7.08 (d, J=10.4 Hz, 1H),2.66-2.58 (m, 3H).

4-Bromo-6-methyl-5-(trifluoromethyl)-1H-indazole. A solution of2-bromo-6-fluoro-4-methyl-3-(trifluoromethyl)benzaldehyde (600 mg, 2.11mmol, 1 eq) and hydrazine monohydrate (2.11 g, 42.1 mmol, 2.05 mL, 20eq) in DMSO (8 mL) was stirred at 60° C. for 2 hours. The mixture wasdiluted with ethyl acetate (50 mL) and washed with water (3×50 mL) andbrine (1×50 mL). The separated organic layer was dried over sodiumsulfate, filtered and concentrated under vacuum. The residue was used inthe next step without further purification.4-Bromo-6-methyl-5-(trifluoromethyl)-1H-indazole (550 mg, 1.97 mmol, 94%yield) was obtained as a white solid.

4-Bromo-6-methyl-1-tetrahydropyran-2-yl-5-(trifluoromethyl) indazole.Toa solution of 4-bromo-6-methyl-5-(trifluoromethyl)-1H-indazole (500mg, 1.79 mmol, 1 eq) in DCM (10 mL) was added 4-methylbenzenesulfonicacid hydrate (34.1 mg, 1791 μmol, 0.1 eq) followed by a solution of DHP(603 mg, 7.17 mmol, 655 μL, 4 eq) in CH₃CN (2 mL). The mixture wasstirred at 25° C. for 16 hours. The mixture was diluted with ethylacetate (100 mL) and washed with water (2×100 mL) and brine (1×50 mL).The organic layer was dried over sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by columnchromatography over silica gel (petroleum ether/ethyl acetate 20/1 to3/1). The desired fractions were collected and concentrated under vacuumto give 4-bromo-6-methyl-1-tetrahydropyran-2-yl-5-(trifluoromethyl)indazole (600 mg, 1.54 mmol, 86% yield, 93% purity) as a light yellowgum. LCMS [MSI, M+1]: 363.

Step A: tert-Butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[6-methyl-1-tetrahydropyran-2-yl-5-(trifluoromethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.A mixture of tert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(400 mg, 848 μmol, 1 eq),4-bromo-6-methyl-1-tetrahydropyran-2-yl-5-(trifluoromethyl) indazole(431 mg, 1.19 mmol, 1.4 eq) Pd₂(dba)₃ (155 mg, 170 μmol, 0.2 eq), RuPhos(158 mg, 339 μmol, 0.4 eq) and Cs₂CO₃ (691 mg, 2.12 mmol, 2.5 eq) intoluene (20 mL) was degassed and purged with N₂ for 3 times, and stirredat 100° C. for 16 hours under N₂. To the mixture was added H₂O (20 mL×1)and ethyl acetate (20 mL×1). The organic phase was separated, filteredand concentrated under reduced pressure to give a residue. The residuewas purified by silica gel chromatography (ethyl acetate/methanol=50/1to 2/1). tert-Butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[6-methyl-1-tetrahydropyran-2-yl-5-(trifluoromethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 535 μmol, 32% yield, 80.7% purity) was obtained as a yellowsolid. LCMS [MSI, M+1]: 754.

Step B:2-[(2S)-4-[2-[[(2S)-1-Methylpyrrolidin-2-yl]methoxy]-7-[6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[6-methyl-1-tetrahydropyran-2-yl-5-(trifluoromethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(470 mg, 503 μmol, 1 eq) in DCM (1 mL) was added TFA (2.29 g, 20.1 mmol,1.49 mL, 40 eq). The mixture was stirred at 25° C. for 1 h. To themixture was added dichloromethane (5 mL) and basified with saturatedaqueous NaHCO₃ to pH=8˜9. The organic phase was separated, dried oversodium sulfate, filtered and concentrated under reduced pressure to give2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(420 mg, 453 μmol, 90% yield, 61.4% purity) as a yellow solid that wasused into next step without further purification. LCMS [MSI, M+1]: 570.

Step C:2-((S)-1-(2-Fluoroacryloyl)-4-(7-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.To a solution of 2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(380 mg, 410 μmol, 1 eq), 2-fluoroprop-2-enoic acid (18.4 mg, 205 μmol,0.5 eq) and TEA (124 mg, 1.23 mmol, 171 μL, 3 eq) in DMF (8 mL) wasadded T3P (391 mg, 614 μmol, 365 μL, 50% purity in DMF, 1.5 eq) at −40°C. Then the mixture was stirred at −40° C. for 0.5 hour and 0° C. foranother 0.5 hour. 2-Fluoroprop-2-enoic acid (11 mg) and T3P (100 μL)were added and the mixture was stirred at −40° C. for further 0.5 hour.The mixture was diluted with water (15 mL) and extracted with EtOAc(2×40 mL). The organic layers were washed with brine (50 mL), dried overNa₂SO₄ and concentrated under vacuum. The residue was purified byprep-HPLC (column: Luna C18 150*25 5 u; mobile phase: [water (0.225%FA)-MeCN]; B %: 22%-42%, 7.8 min) and (column: Phenomenex Gemini 150*25mm*10 μm; mobile phase: [water (0.04% NH₃H₂O+10 mM NH₄HCO₃)-MeCN]; B %:50%-68%, 12 min). The desired fractions were collected and lyophilizedto give title compound2-((S)-1-(2-fluoroacryloyl)-4-(7-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrileas white solid. LCMS [ESI, M+1]: 642.

Example 556

2-[(2S)-1-(2-Fluoroprop-2-enoyl)-4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

3-Bromo-1-(methoxymethoxy)naphthalene. To a solution of4-bromonaphthalen-2-ol (3.50 g, 15.7 mmol, 1.0 eq) in DMF (35.0 mL) wasadded NaH (941 mg, 23.5 mmol, 60% purity, 1.50 eq). After addition, themixture was stirred at this temperature for 0.5 hour, and thenchloro(methoxy)methane (5.90 g, 73.3 mmol, 5.57 ml, 4.67 eq) was addeddropwise at 0° C. The mixture was warmed to 30° C. and stirred forfurther 1 hour. After completion, the combined reaction mixture wasdiluted with water (100 mL) and extracted with EtOAc (3×50.0 mL). Thecombined organic layers were washed with saturated brine (200 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (SiO₂,petroleum ether/ethyl acetate=1/0 to 100/1). Compound3-bromo-1-(methoxymethoxy)naphthalene (3.50 g, 13.1 mmol, 84% yield) wasobtained as a red oil.

¹H NMR (400 MHz, chloroform-d) δ 8.19-8.12 (m, 1H), 7.78-7.71 (m, 1H),7.61-7.57 (m, 1H), 7.52-7.44 (m, 2H), 7.40 (d, J=2.0 Hz, 1H), 5.29 (s,2H), 3.53 (s, 3H).

Step A: tert-Butyl(2S)-2-(cyanomethyl)-4-[7-[3-(methoxymethoxy)-1-naphthyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of tert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(800 mg, 1.70 mmol, 1.0 eq) and 1-bromo-3-(methoxymethoxy)naphthalene(680 mg, 2.54 mmol, 1.50 eq) in toluene (10.0 mL) was added Cs₂CO₃ (2.21g, 6.79 mmol, 4.00 eq), RuPhos (158 mg, 339 μmol, 0.20 eq) and Pd₂(dba)₃(233 mg, 254 μmol, 0.15 eq). The mixture was stirred at 90° C. for 6hours. The reaction mixture was diluted with H₂O 100 mL and extractedwith ethyl acetate (3×100 mL). The combined organic layers wereconcentrated under reduced pressure to give a residue. The residue wasfurther purified by reverse phase flash [water (0.1% formicacid)/acetonitrile)]. The mixture was adjusted pH=7 with NaHCO₃ aqueoussolution and extracted with ethyl acetate (3×50.0 mL). The combinedorganic layers were washed with saturated brine (100 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give theproduct. Compound tert-butyl(2S)-2-(cyanomethyl)-4-[7-[3-(methoxymethoxy)-1-naphthyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(280 mg, 426 μmol, 25% yield) was obtained as a yellow solid. LCMS [ESI,M+1]: 658.

¹H NMR (400 MHz, chloroform-d) δ 8.09 (d, J=8.0 Hz, 1H), 7.75 (d, J=8.2Hz, 1H), 7.45 (t, J=7.0 Hz, 1H), 7.40-7.34 (m, 1H), 7.16 (d, J=2.0 Hz,1H), 6.87 (d, J=2.4 Hz, 1H), 5.30 (s, 2H), 4.63 (br s, 1H), 4.40 (dd,J=4.8, 10.4 Hz, 1H), 4.33-4.22 (m, 2H), 4.21-4.16 (m, 1H), 4.09-3.86 (m,3H), 3.54 (s, 3H), 3.51-3.40 (m, 1H), 3.37-3.17 (m, 3H), 3.15-2.96 (m,3H), 2.89-2.73 (m, 3H), 2.72-2.64 (m, 1H), 2.49 (s, 3H), 2.33-2.25 (m,1H), 2.13-2.05 (m, 1H), 1.91-1.78 (m, 3H), 1.52 (s, 9H).

Step B:2-[(2S)-4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-2-(cyanomethyl)-4-[7-[3-(methoxymethoxy)-1-naphthyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(260 mg, 395 μmol, 1.0 eq) in dioxane (2.0 mL) was added HCl·dioxane (4M, 98.8 μL, 1.0 eq). The mixture was stirred at 20° C. for 1 hour. Aftercompletion, the reaction mixture was concentrated under reduced pressureto give a residue. The residue was adjusted pH=7 with saturated ofNaHCO₃ aqueous solution and extracted with ethyl acetate (3×20.0 mL).The combined organic layers were washed with saturated brine (30.0 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive the residue. Compound2-[(2S)-4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(200 mg, 373 μmol, 94% yield, 96% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 514.

Step C:2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(200 mg, 389 μmol, 1.0 eq) and 2-fluoroprop-2-enoic acid (105 mg, 1.17mmol, 3.0 eq) in DMF (4.00 mL) was added TEA (158 mg, 1.56 mmol, 217 μL,4.0 eq) and T3P (743 mg, 1.17 mmol, 695 μL, 50% purity, 3.0 eq) at 0° C.The mixture was stirred at 0° C. for 0.5 hour. After completion, thereaction mixture was diluted with H2O (10.0 mL) and extracted with DCM(3×10.0 mL). The combined organic layers were washed with saturatedbrine (20.0 mL), dried over Na2SO4, filtered and concentrated underreduced pressure to give a residue. The residue was purified by columnchromatography (Al2O3, petroleum ether/ethyl acetate=10/1 toDCM/MeOH=5/1), and the residue was purified by prep-HPLC (column:Phenomenex Gemini 150*25 mm*10 μm; mobile phase: [water (0.04% NH3H2O+10mM NH4HCO3)-MeCN]; B %: 45%-75%, 12 min). Title compound2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(50.0 mg, 85.0 μmol, 22% yield, 99.6% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 586.

¹H NMR (400 MHz, chloroform-d) δ 7.94 (br d, J=8.4 Hz, 1H), 7.62 (d,J=8.0 Hz, 1H), 7.40 (t, J=7.2 Hz, 1H), 7.31-7.26 (m, 1H), 6.86 (s, 1H),6.52 (br s, 1H), 5.51-5.29 (m, 1H), 5.25 (dd, J=3.6, 16.8 Hz, 1H),4.95-4.35 (m, 2H), 4.24 (dd, J=4.4, 11.2 Hz, 1H), 4.15-3.93 (m, 3H),3.85-3.69 (m, 1H), 3.45-3.26 (m, 1H), 3.25-3.18 (m, 2H), 3.17-2.95 (m,2H), 2.94-2.73 (m, 3H), 2.72-2.62 (m, 51H), 2.60-2.50 (m, 1H), 2.45-2.35(m, 1H), 2.15-2.06 (m, 1H), 2.01-1.93 (m, 1H), 1.88-1.74 (m, 3H).

Example 557

2-[(2S)-4-[7-(8-Chloro-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile

Step A: Benzyl4-[(3S)-4-tert-butoxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate.To a solution of [(2R)-1-methylpyrrolidin-2-yl]methanol (934 mg, 8.11mmol, 3.0 eq) and t-BuONa (780 mg, 8.11 mmol, 3.0 eq) in toluene (15.0mL) was added a solution of benzyl4-[(3S)-4-tert-butoxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(1.5 g, 2.70 mmol, 1.0 eq) in toluene (10.0 mL) dropwise at 0° C. Thereaction mixture was stirred at 0° C. for another 0.5 hr. Aftercompletion, the reaction was quenched with water (30.0 mL). The crudemixture was extracted with ethyl acetate (2×50.0 mL). Combine extractswere washed with brine (100 mL), dried with Na₂SO₄, the solvent was thenremoved under vacuum. The residue was purified by reverse phase flashHPLC [C18, 0.1% FA in water, 0-65% MeCN] and was acidified with NaHCO₃to pH=8 and extracted with ethyl acetate (2×150 mL). The organic layerswere dried over Na₂SO₄, filtered and concentrated under vacuum Compoundbenzyl4-[(3S)-4-tert-butoxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(820 mg, 1.26 mmol, 47% yield, 93% purity) was obtained as white solid.LCMS [ESI, M+1]: 606.

¹H NMR (400 MHz, chloroform-d) δ 7.42-7.29 (m, 5H), 5.18 (s, 2H), 4.69(br d, J=18.6 Hz, 1H), 4.59 (br s, 1H), 4.44 (d, J=18.8 Hz, 1H), 4.34(br s, 1H), 4.05-3.69 (m, 4H), 3.42 (br s, 1H), 3.24 (br d, J=13.0 Hz,2H), 3.09 (br t, J=7.6 Hz, 1H), 3.02-2.90 (m, 1H), 2.81-2.56 (m, 5H),2.47 (s, 3H), 2.28 (dt, J=7.2, 9.4 Hz, 1H), 2.05-1.99 (m, 1H), 1.89-1.67(m, 4H), 1.51 (s, 9H).

Step B: tert-Butyl(2S)-2-(cyanomethyl)-4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.NH₃ was bubbled into MeOH (10.0 mL) of at −70° C. for 0.5 hr. Benzyl4-[(3S)-4-tert-butoxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[[(2R)-1-methylpyrrolidin-2-Yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(820 mg, 1.35 mmol, 1.0 eq) and Pd/C (250 mg, 10% purity) was added tothe above mixture and MeOH (10.0 mL), then the mixture was degassed andpurged with H₂ 3 times, and then the mixture was stirred at 20° C. for0.5 hr under H₂ (15 psi). After completion, the crude mixture wasfiltered through a pad of celite. The cake was washed with MeOH (50.0mL) and the filtrate dried under high vacuum. Compound tert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(600 mg, 1.27 mmol, 94% yield, 100% purity) was obtained as white solidand used into the next step without further purification. LCMS [ESI,M+1]: 472.

Step C:tert-Butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.A mixture of tert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(550 mg, 1.17 mmol, 1.0 eq), 1-bromo-8-chloro-naphthalene (845 mg, 3.50mmol, 3.0 eq), Pd₂(dba)₃ (160 mg, 175 μmol, 0.15 eq), Xantphos (135 mg,233 μmol, 0.20 eq) and Cs₂CO₃ (1.14 g, 3.50 mmol, 3.0 eq) in toluene(10.0 mL) was degassed and purged with N₂ 3 times, and then the mixturewas stirred at 90° C. for 8 hrs under N₂. After completion, the reactionwas washed with HCl (2N 2×15 mL) aqueous solution. The aqueous phase wasbasified with NaHCO₃ to pH 8 and extracted with ethyl acetate (2×50 mL).The organic layers were dried over Na₂SO₄, filtered and concentratedunder vacuum. The residue was purified by reverse phase flash HPLC [C18,0.1% FA in water, 0-65% MeCN] and was acidified with NaHCO₃ to pH=8 andextracted with ethyl acetate (2×150 mL). The organic layers were driedover Na₂SO₄, filtered and concentrated under vacuum. Compoundtert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(600 mg, 930 μmol, 80% yield, 98% purity) was obtained as white solid.LCMS [ESI, M+1]: 632.

¹H NMR (400 MHz, chloroform-d) δ=7.75 (br d, J=8.2 Hz, 1H), 7.61 (t,J=8.0 Hz, 1H), 7.52 (d, J=7.5 Hz, 1H), 7.44 (td, J=7.8, 15.2 Hz, 1H),7.33 (t, J=7.8 Hz, 1H), 7.27-7.17 (m, 1H), 4.61 (br s, 1H), 4.48-4.34(m, 2H), 4.10-3.91 (m, 3H), 3.90-3.78 (m, 1H), 3.63-3.53 (m, 1H), 3.34(br dd, J=3.6, 13.8 Hz, 1H), 3.30-3.01 (m, 5H), 2.95 (dt, J=3.5, 12.3Hz, 1H), 2.89-2.75 (m, 1H), 2.70 (br s, 2H), 2.57 (br d, J=14.2 Hz, 1H),2.53-2.46 (m, 3H), 2.35-2.25 (m, 1H), 2.13-2.06 (m, 1H), 1.93-1.66 (m,3H), 1.52 (s, 9H).

Step D:2-[(2S)-4-[7-(8-Chloro-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(200 mg, 316 μmol, 1.0 eq) in dioxane (2.0 mL) was added HCl/dioxane (4M, 2.0 mL, 25.3 eq). The mixture was stirred at 20° C. for 0.5 hourunder N₂. After completion, the organic solvent was removed undervacuum. The obtained product was adjusted with saturated aqueous NaHCO₃to Ph=8, then concentrated. The aqueous phase was extracted with ethylacetate (3×10.0 mL), the combined organic layer was dried over Na₂SO₄,filtered and concentrated. The crude product2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(145 mg, 259 μmol, 82% yield, 95% purity) was obtained as yellow solidand used into the next step without further purification. LCMS [ESI,M+1]: 532

Step E:2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(125 mg, 235 μmol, 1.0 eq), 2-fluoroprop-2-enoic acid (42.3 mg, 470μmol, 2.0 eq) in ethyl acetate (2.0 mL) was added TEA (190 mg, 1.88mmol, 262 μL, 8.0 eq) and T3P (449 mg, 705 μmol, 419 μL, 50% purity, 3.0eq) at 0° C. The mixture was stirred at 20° C. for 1 hour. Aftercompletion, the organic solvent was washed with water (5.0 mL). Theaqueous phase was extracted with ethyl acetate (3×10 mL). The combinedorganic extracts were washed with brine (20.0 mL), dried with Na₂SO₄ thesolvent was then removed under vacuum. The residue was purified bycolumn chromatography (basic Al₂O₃, petroleum ether:ethyl acetate=3:1 toethyl acetate:methanol=50:1), then the crude product was concentratedand re-purified by prep-HPLC (column: Phenomenex Gemini 150×25 mm×10 μm;mobile phase: [water (0.05% ammonium hydroxide v/v)-MeCN]; B %: 55%-85%,11.5 min) and lyophilization. Title compound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile(22.5 mg, 37.1 μmol, 16% yield, 99% purity) was obtained as white solid.LCMS [ESI, M+1]: 605.

¹H NMR (400 MHz, chloroform-d) δ 7.76 (br d, J=8.4 Hz, 1H), 7.62 (t,J=7.6 Hz, 1H), 7.53 (d, J=7.2 Hz, 1H), 7.49-7.40 (m, 1H), 7.34 (t, J=7.8Hz, 1H), 7.26-7.18 (m, 1H), 5.51-5.32 (m, 1H), 5.26 (br dd, J=3.2, 16.8Hz, 1H), 4.90 (br s, 1H), 4.49-4.34 (m, 2H), 4.24-4.01 (m, 3H),3.97-3.78 (m, 2H), 3.64-3.55 (m, 1H), 3.44 (br s, 1H), 3.32-2.95 (m,5H), 2.94-2.43 (m, 7H), 2.38-2.20 (m, 1H), 2.14-1.99 (m, 1H), 1.91-1.71(m, 3H).

Example 558

2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((2R,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

Step A: Benzyl4-[(3S)-4-tert-butoxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[[(2R,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate.To a solution of [(2R,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methanol(169 mg, 1.27 mmol, 1.5 eq) in toluene (4.0 mL) was added t-BuONa (163mg, 1.69 mmol, 2.0 eq) at 0° C., after the reaction mixture was stirredat 0° C. for 0.5 hour, benzyl4-[(3S)-4-tert-butoxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(470 mg, 847 μmol, 1.0 eq) was added to the mixture, the reactionmixture was stirred at 0° C. for 0.5 hour. After completion, thereaction mixture was added to water (10 mL), then extracted with ethylacetate (2×10.0 mL), the organic layer was dried over Na₂SO₄, filteredand concentrated. The residue was purified by column chromatography(SiO₂, petroleum ether/ethyl acetate=3/1 to ethyl acetate/methanol=20/1)to give benzyl4-[(3S)-4-tert-butoxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[[(2R,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(330 mg, 484 μmol, 57% yield, 92% purity) as white solid. LCMS [ESI,M+1]: 624.

¹H NMR (400 MHz, chloroform-d) δ 7.40-7.30 (m, 5H), 5.24-5.03 (m, 3H),4.69 (d, J=18.8 Hz, 1H), 4.61-4.53 (m, 1H), 4.51-4.38 (m, 2H), 4.23 (dd,J=7.6, 10.4 Hz, 1H), 4.08-3.73 (m, 4H), 3.52-3.11 (m, 4H), 3.04-2.91 (m,1H), 2.81-2.57 (m, 5H), 2.55-2.36 (m, 5H), 2.11-1.99 (m, 1H), 1.51 (s,9H).

Step B: tert-Butyl(2S)-2-(cyanomethyl)-4-[2-[[(2R,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of benzyl4-[(3S)-4-tert-butoxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[[(2R,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(330 mg, 529 μmol, 1.0 eq) in methanol (3.0 mL) and NH₃·MeOH (529 μmol,3 mL, 20% purity, 1.0 eq) was added Pd/C (50 mg, 529 μmol, 10% purity)under N₂. The suspension was degassed under vacuum and purged with H₂several times. The mixture was stirred under H₂ (15 psi) at 15° C. for 3hours. After completion, the mixture was filtered, and the filter cakewas washed with THF (2×3.0 mL), the filtrate was concentrated. Theresidue was purified by reverse phase flash chromatography (0.1% FA inMeCN). The mixture was adjusted with NaHCO₃ solid to pH˜8, thenconcentrated. The aqueous layer (20.0 mL) was extracted with ethylacetate (2×15.0 mL), the organic layer was dried over Na₂SO₄, filteredand concentrated to give tert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2R,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(150 mg, 299 μmol, 58% yield, 98% purity) as white solid. LCMS [ESI,M+1]: 490.

Step C:tert-Butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.To a solution of tert-butyl(2S)-2-(cyanomethyl)-4-[2-[((2R,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(150 mg, 306 μmol, 1.0 eq) and 1-bromo-8-chloro-naphthalene (148 mg, 618μmol, 2.0 eq) in toluene (3.0 mL) was added XantPhos (35.5 mg, 61.3μmol, 0.2 eq), Pd₂(dba)₃ (42.1 mg, 45.9 μmol, 0.15 eq), and Cs₂CO₃ (399mg, 1.23 mmol, 4.0 eq), the reaction mixture was stirred at 90° C. for12 hours under N₂. After completion, the reaction mixture was filteredthrough celite, and the filtrate was washed with 1N aqueous HCl (2×10.0mL), the aqueous layer was adjusted to pH-S with solid Na₂CO₃, thenextracted with ethyl acetate (2×15.0 mL), the organic layer was driedover Na₂SO₄, filtered and concentrated. The residue was purified byreverse phase flash chromatography (0.1% FA in MeCN). The obtainedproduct was adjusted with solid NaHCO₃ to pH˜8, and concentrated. Theaqueous layer (20 mL) was extracted with ethyl acetate (2×15.0 mL), theorganic layer was dried over Na₂SO₄, filtered and concentrated. Theproducttert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(85 mg, 129 μmol, 43% yield, 98% purity) was obtained as white solid.LCMS [ESI, M+1, M+23]: 650, 672.

¹H NMR (400 MHz, chloroform-d) δ 7.76 (br d, J=8.0 Hz, 1H), 7.62 (t,J=8.0 Hz, 1H), 7.52 (d, J=7.6 Hz, 1H), 7.49-7.40 (m, 1H), 7.34 (t, J=7.8Hz, 1H), 7.26-7.17 (m, 1H), 5.24-5.03 (m, 1H), 4.67-4.55 (m, 1H),4.52-4.36 (m, 2H), 4.23 (dd, J=7.6, 10.4 Hz, 1H), 4.13-3.77 (m, 4H),3.65-3.52 (m, 1H), 3.43-2.86 (m, 7H), 2.84-2.64 (m, 3H), 2.62-2.38 (m,5H), 2.16-1.98 (m, 1H), 1.52 (s, 9H).

Step D:2-[(2S)-4-[7-(8-Chloro-1-naphthyl)-2-[[(2R,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(85.0 mg, 131 μmol, 1.0 eq) in dioxane (1.0 mL) was added 4 MHCl/dioxane (1.0 mL), the reaction mixture was stirred at 20° C. for 4hours. After completion, the reaction mixture was concentrated, themixture was added dichloromethane (10 mL), then adjusted with saturatedaqueous Na₂CO₃ to pH˜8, the organic layer was separated, then dried overNa₂SO₄, filtered and concentrated. The product2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(90 mg, crude) was obtained as brown solid. LCMS [ESI, M+1]: 550.

Step E:2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((2R,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile.To a solution of2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(90.0 mg, 120 μmol, 73% purity, 1.0 eq) and 2-fluoroprop-2-enoic acid(21.7 mg, 241 μmol, 2.0 eq) in ethyl acetate (2.0 mL) was added T3P (230mg, 361 μmol, 215 μL, 50% purity, 3.0 eq) and TEA (97.6 mg, 962 μmol,134 μL, 8.0 eq), the reaction mixture was stirred at 20° C. for 1 hour.After completion, water was added (10.0 mL), then the organic layer wasseparated, the aqueous layer was extracted with ethyl acetate (2×10.0mL). The combined organic layer was dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography (SiO₂,petroleum ether/ethyl acetate=3/1 to ethyl acetate:methanol=10:1). Thecrude product was re-purified by prep-HPLC (column: Phenomenex Gemini150*25 mm*10 μm; mobile phase: [water (0.04% NH₃H₂O+10 mMNH₄HCO₃)-MeCN]; B %: 48%-78%, 12 min), the obtained product wasconcentrated, and then lyophilized. The product title compound2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((2R,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile(10.9 mg, 17.3 μmol, 14% yield, 99% purity) was obtained as white solid.LCMS [ESI, M+1]: 622.

¹H NMR (400 MHz, Chloroform-d) δ 7.76 (d, J=8.0 Hz, 1H), 7.63 (t, J=7.6Hz, 1H), 7.53 (d, J=7.2 Hz, 1H), 7.49-7.41 (m, 1H), 7.34 (t, J=7.8 Hz,1H), 7.27-7.18 (m, 1H), 5.50-5.34 (m, 1H), 5.26 (dd, J=3.6, 16.8 Hz,1H), 5.22-5.04 (m, 1H), 4.98-4.72 (m, 1H), 4.54-4.37 (m, 2H), 4.30-4.02(m, 3H), 3.96-3.75 (m, 2H), 3.66-3.54 (m, 1H), 3.51-2.99 (m, 6H),2.98-2.67 (m, 3H), 2.64-2.36 (m, 6H), 2.14-1.97 (m, 1H).

Example 559

2-[(2S)-4-[2-[2-(Dimethylamino)ethoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile

Step A:2-[(7-Benzyl-4-methoxy-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl)oxy]-N,N-dimethyl-ethanamine.To the solution of7-benzyl-2-chloro-4-methoxy-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (5 g,17.3 mmol, 1 eq), 2-(dimethylamino)ethanol (3.08 g, 34.5 mmol, 3.46 mL,2 eq), Cs₂CO₃ (5.62 g, 17.3 mmol, 1 eq) and BINAP (2.15 g, 3.45 mmol,0.2 eq) in toluene (100 mL) was added Pd(OAc)₂ (387 mg, 1.73 mmol, 0.1eq) under N₂. The suspension was degassed under vacuum and purged withN₂ several times. The mixture was stirred under N₂ at 100° C. for 12hours. The reaction mixture was filtered. To the filtrate was added HO(2 M, 200 mL), then separated. The aqueous phase was basified withNaHCO₃ and K₂CO₃ to PH=8˜9, then extracted with EtOAc (5×80 mL). Thecombined organic phase was washed with brine (100 mL), dried withanhydrous Na₂SO₄, filtered and concentrated in vacuum to give2-[(7-benzyl-4-methoxy-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl)oxy]-N,N-dimethyl-ethanamine(4.8 g, 12.6 mmol, 73% yield, 90% purity) as a brown oil which was usedfor next step without further purification.

¹H NMR (400 MHz, chloroform-d) δ=7.40-7.28 (m, 5H), 4.40 (t, J=6.0 Hz,2H), 3.96 (s, 3H), 3.69 (s, 2H), 3.50 (s, 2H), 2.76-2.69 (m, 4H),2.62-2.56 (m, 2H), 2.32 (s, 6H).

Step B:2-[(4-Methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy]-N,N-dimethyl-ethanamine.To the solution of2-[(7-benzyl-4-methoxy-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl)oxy]-N,N-dimethyl-ethanamine(4.8 g, 14.0 mmol, 1 eq) in MeOH (100 mL) was added Pd(OH)₂/C (2 g, 10%purity) under N₂. The suspension was degassed under vacuum and purgedwith H₂ several times. The mixture was stirred under H₂ (15 psi) at 40°C. for 18 hours. To the mixture was added HCl/MeOH (4 M, 7.01 mL, 2 eq).The suspension was degassed under vacuum and purged with H₂ severaltimes. The mixture was stirred under H₂ (15 psi) at 40° C. for 2 hours.The mixture was filtered, the filter cake was washed with NH₃·MeOH (10%,3×30 mL). The filtrate was concentrated under vacuum. The residue wasdissolved with water (10 mL) and EtOAc (10 mL), then the mixture wasbasified with K₂CO₃ to pH=11. The mixture was extracted with EtOAc (8×20mL). The combined organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated under vacuum to give2-[(4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy]-N,N-dimethyl-ethanamine(2.58 g, 8.69 mmol, 62% yield, 85% purity) as a brown oil which was usedfor next step without further purification. LCMS [ESI, M+1]: 253.

Step C:2-[[4-Methoxy-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]-N,N-dimethyl-ethanamine.To the solution of2-[(4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy]-N,N-dimethyl-ethanamine(2.28 g, 7.68 mmol, 1 eq), 1-bromo-8-methyl-naphthalene (2.55 g, 11.5mmol, 1.5 eq), Cs₂CO₃ (7.51 g, 23.0 mmol, 3 eq) and Xantphos (889 mg,1.54 mmol, 0.2 eq) in toluene (70 mL) was added Pd₂(dba)₃ (703 mg, 768μmol, 0.1 eq) under N₂. The suspension was degassed under vacuum andpurged with N₂ several times. The mixture was stirred under N₂ at 100°C. for 16 hours. The reaction mixture was filtered, the filtrate wasconcentrated under vacuum. The residue was purified by silica gelchromatography (PE:EtOAc=10:1˜0:1 to EtOAc:MeOH=1:0˜10.1) to give2-[[4-methoxy-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]-N,N-dimethyl-ethanamine(3.2 g, 7.34 mmol, 95% yield, 90% purity) as a brown solid. LCMS [ESI,M+1]: 393.

¹H NMR (400 MHz, chloroform-d) δ=7.69 (d, J=8.0 Hz, 1H), 7.64 (d, J=7.6Hz, 1H), 7.40 (t, J=7.6 Hz, 1H), 7.33 (t, J=7.6 Hz, 1H), 7.27-7.22 (m,2H), 4.44 (t, J=6.4 Hz, 2H), 4.17-4.05 (m, 1H), 4.03 (s, 3H), 3.81 (d,J=17.6 Hz, 1H), 3.57-3.48 (m, 1H), 3.20 (dt, J=4.0, 11.2 Hz, 1H),2.94-2.82 (m, 4H), 2.75 (t, J=6.4 Hz, 2H), 2.67 (br d, J=16.4 Hz, 1H),2.34 (s, 6H).

Step D:2-[2-(Dimethylamino)ethoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-ol.To the solution of EtSH (1.96 g, 31.5 mmol, 2.33 mL, 3.64 eq) in DMF (60mL) was added NaH (693 mg, 17.3 mmol, 60% purity, 2 eq), the mixture wasstirred at 10° C. for 0.5 hour. Then2-[[4-methoxy-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]-N,N-dimethyl-ethanamine(3.4 g, 8.66 mmol, 1 eq) in DMF (10 mL) was added, the mixture washeated to 60° C. and stirred for 1 hour. The mixture was poured into icewater (200 mL) and extracted with EtOAc (30 mL). The aqueous phase wasacidified with HCl (2 M) to PH=7˜8, then extracted with EtOAc (6×80 mL).The combined organic layers were dried over anhydrous Na₂SO₄, filteredand concentrated under vacuum. The residue was triturated withPE:EtOAc=5:1 to give2-[2-(dimethylamino)ethoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-ol(2.4 g, 6.28 mmol, 72% yield, 99% purity) as a white solid. LCMS [ESI,M+1]: 379.

Step E:[2-[2-(Dimethylamino)ethoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]trifluoromethanesμLfonate. To die solution of2-[2-(dimethylamino)ethoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-ol(1 g, 2.64 mmol, 1 eq) and TEA (668 mg, 6.61 mmol, 919 μL, 2.5 eq) inDCM (20 mL) was added Tf₂O (1.12 g, 3.96 mmol, 654 μL, 1.5 eq) at −40°C., the mixture was stirred at −40° C. for 10 min. To the mixture wasadded water (10 mL), then separated. The aqueous phase was extractedwith EtOAc (20 mL). The combined organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated under vacuum. The residuewas purified by silica gel chromatography (PE:EtOAc=5:1˜0:1) to give[2-[2-(dimethylamino)ethoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]trifluoromethanesμLfonate (650 mg, 1.15 mmol, 43% yield, 90% purity) asa brown oil.

Step F:2-[(2S)-4-[2-[2-(Dimethylamino)ethoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To the solution of[2-[2-(dimethylamino)ethoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]trifluoromethanesμLfonate(350 mg, 685 μmol, 1 eq) and 2-[(2S)-piperazin-2-yl]acetonitrile (111mg, 754 μmol, 1.1 eq) in DMAC (4 mL) was added DIEA (177 mg, 1.37 mmol,239 μL, 2 eq), the mixture was stirred at 10° C. for 10 min. The mixturewas purified by reversed phase flash column (MeCN/Water (0.1% FA)=40%)to give2-[(2S)-4-[2-[2-(dimethylamino)ethoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(60 mg, 121 μmol, 18% yield, 98% purity) as a brown oil. LCMS [ESI,M+1]: 486.

Step F:2-[(2S)-4-[2-[2-(Dimethylamino)ethoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.To the solution of2-[(2S)-4-[2-[2-(dimethylamino)ethoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(60 mg, 123 μmol, 1 eq), 2-fluoroprop-2-enoic acid (22.2 mg, 247 μmol, 2eq) and TEA (100 mg, 988 μmol, 138 μL, 8 eq) in EtOAc (1.2 mL) was addedT3P (236 mg, 370 μmol, 220 μL, 50% purity, 3 eq) at 0° C., the mixturewas stirred at 10° C. for 0.5 hour. Water (5 mL) was added into themixture. The mixture was extracted with EtOAc (2×8 mL). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by Al₂O₃chromatography (EtOAc:MeOH=1:0˜20:1). Then the residue was purified byprep-HPLC (column: Gemini 150*25 5μ; mobile phase: [water (0.05%ammonium hydroxide v/v)-MeCN]; B %: 53%-83%, 12 min) to give titlecompound2-[(2S)-4-[2-[2-(dimethylamino)ethoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile(39.5 mg, 70.4 μmol. 57% yield, 99.4% purity) as a gray solid. LCMS[ESI, M+1]: 558.

¹H NMR (400 MHz, chloroform-d) δ=7.70 (br d, J=8.4 Hz, 1H), 7.65 (t,J=8.0 Hz, 1H), 7.46-7.38 (m, 1H), 7.35 (t, J=7.6 Hz, 1H), 7.27-7.18 (m,2H), 5.52-5.33 (m, 1), 5.26 (dd, J=3.6, 16.8 Hz, 1H), 4.88 (br s, 1H),4.47-4.37 (m, 2H), 4.31-4.18 (m, 1H), 4.17-4.01 (m, 2H), 3.94-3.84 (m,1H), 3.77 (d, J=18.0 Hz, 1H), 3.58-3.41 (m, 2H), 3.25-2.95 (m, 4H), 2.92(s, 3H), 2.90-2.77 (m, 2H), 2.77-2.70 (m, 2H), 2.68-2.56 (m, 1H), 2.34(d, J=3.6 Hz, 6H).

Example 560

2-[(2S)-4-[2-[[(2S,4R)-4-Fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile

1-tert-Butyl-2-methyl (2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylate. Toa solution of(2S,4R)-1-tert-butoxycarbonyl-4-fluoro-pyrrolidine-2-carboxylic acid(2.0 g, 8.58 mmol, 1.0 eq) and Ag₂O (3.97 g, 17.2 mmol, 2.0 eq) in CH₃CN(20.0 mL) was added MeI (2.43 g, 17.2 mmol, 1.07 mL, 2.0 eq) at 0° C. inportions, the reaction mixture was stirred at 15° C. for 12 hours. Aftercompletion, the reaction mixture was added to water (30.0 mL), then theorganic layer was separated, the aqueous phase was extracted with ethylacetate (30.0 mL×2), the combined organic layer was dried over Na₂SO₄,filtered and concentrated. The residue was purified by columnchromatography (SiO₂, petroleum ether:ethyl acetate=3:1 to ethylacetate:methanol=10:1). The product 1-tert-butyl-2-methyl (2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylate (1.98 g, 8.01 mmol, 93% yield)was obtained as colorless oil.

¹H NMR (400 MHz, Chloroform-d) δ 5.29-5.15 (m, 1H), 4.49-4.38 (m, 1H),3.92-3.74 (m, 1H), 3.68 (s, 3H), 3.60-3.56 (m, 1H), 2.63-2.54 (m, 1H),2.17-2.05 (m, 1H), 1.44 (d, J=18.0 Hz, 9H).

[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methanol. To a solution of1-tert-butyl-2-methyl (2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylate(1.98 g, 8.0 mmol, 1.0 eq) in THF (20.0 mL) was added LiAlH₄ (912 mg,24.0 mmol, 3.0 eq) slowly at −40° C., after completion the mixture wasstirred at −40° C. for 0.5 hour, then the mixture was warmed to 70° C.and stirred at this temperature for 3 hours. After completion, thereaction mixture was quenched by addition a solution of Na₂SO₄ (6.0 mL)at 0° C., and then diluted with THF (10.0 mL), then filtered and thesolid was washed with ethyl acetate (30.0 mL). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated under reducedpressure to give [(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methanol(800 mg, 6.01 mmol, 75% yield) as yellow oil.

¹H NMR (400 MHz, Chloroform-d) δ 5.13-4.97 (m, 1H), 3.67-3.63 (m, 1H),3.51-3.37 (m, 2H), 2.95 (s, 1H), 2.74-2.68 (m, 1H), 2.63-2.51 (m, 1H),2.33 (s, 3H), 2.07-2.02 (m, 1H), 1.99-1.95 (m, 1H).

Step A: Benzyl4-[(3S)-4-tert-butoxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate.A mixture of [(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methanol (480mg, 3.6 mmol, 2.0 eq) and t-BuONa (295 mg, 3.1 mmol, 1.7 eq) in toluene(8.0 mL) was degassed and purged with N₂ for 3 times and the mixture wasstirred at 0° C., then benzyl4-[(3S)-4-tert-butoxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(1 g, 1.8 mmol, 1.0 eq) in toluene (8.0 mL) was added. The mixture wasstirred at 0° C. for 0.5 hour under N₂. After completion, the mixturewas quenched by addition H₂O (25.0 mL), and then extracted with ethylacetate (30.0 mL×3). The combined organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by reverse phase flash HPLC (¹⁸C, 0.1% FA in water,0-60% MeCN). The obtained product was adjusted with saturated aqueousNaHCO₃ to pH˜8, then concentrated, the aqueous layer was extracted withethyl acetate (100.0 mL×3), the combined organic layer was dried overNa₂SO₄, filtered and concentrated to give benzyl4-[(3S)-4-tert-butoxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(860 mg, 1.38 mmol, 76% yield, 100% purity) as a white solid. LCMS [ESI,M+1]: 624.

¹H NMR (400 MHz, Chloroform-d) δ 7.31-7.25 (m, 5H), 5.15-5.02 (m, 3H),4.63-4.58 (m, 1H), 4.51 (br s, 1H), 4.39-4.31 (m, 2H), 4.16-4.12 (m,1H), 3.99-3.88 (m, 3H), 3.71 (br d, J=11.2 Hz, 1H), 3.52-3.41 (m, 1H),3.36 (br s, 1H), 3.19-3.16 (m, 2H), 2.99-2.86 (m, 2H), 2.71-2.48 (m,5H), 2.43 (s, 3H), 2.76-2.17 (m, 1H), 1.96-1.80 (m, 1H), 1.74 (br s,1H), 1.43 (s, 9H).

Step B:tert-butyl-(2S)-2-(cyanomethyl)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of benzyl4-[(3S)-4-(tert-butoxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(860 mg, 1.4 mmol, 1.0 eq) in MeOH (20.0 mL) and NH₃·MeOH (10.0 mL, 50%w/w) was added Pd/C (200 mg, 10% purity, 1.0 eq) under N₂. Thesuspension was degassed under vacuum and purged with H₂ several times.The mixture was stirred under H₂ (15 psi) at 25° C. for 1 hour. Aftercompletion, the reaction mixture was filtered and concentrated underreduced pressure to givetert-butyl-(2S)-2-(cyanomethyl)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(620 mg, crude) as a white solid. The crude product was used into thenext step without further purification. LCMS [ESI, M+1]: 490.

¹H NMR (400 MHz, Chloroform-d) δ 5.16-5.02 (m, 1H), 4.51 (br s, 1H),4.31 (dd, J=4.8, 11.2 Hz, 1H), 4.13 (dd, J=6.0, 11.2 Hz, 1H), 3.87 (s,2H), 3.76 (d, J=12.4 Hz, 1H), 3.52-3.41 (m, 1H), 3.14 (dd, J=3.6, 13.6Hz, 2H), 3.06-3.03 (m, 1H), 2.99-2.88 (m, 3H), 2.74-2.48 (m, 6H), 2.43(s, 3H), 2.29-2.18 (m, 1H), 1.96-1.80 (m, 1H), 1.68-1.59 (m, 2H), 1.44(s, 9H).

Step C:tert-Butyl-(2S)-2-(cyanomethyl)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.A mixture oftert-butyl-(2S)-2-(cyanomethyl)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(600 mg, 1.2 mol, 1.0 eq), 1-bromo-8-methyl-naphthalene (812 mg, 3.7mmol, 3.0 eq), Pd₂(dba)₃ (168 mg, 184 μmol, 0.15 eq), Cs₂CO₃ (1.2 g, 3.7mmol, 3.0 eq) and Xantphos (142 mg, 246 μmol, 0.2 eq) in toluene (5.0mL) was degassed and purged with N₂ for 3 times, and then the mixturewas stirred at 90° C. for 12 hours under N₂. Ater completion, thereaction mixture was filtered and concentrated under reduced pressure togive a residue, and then the residue was dissolved with EA 15.0 mL, thenwas adjusted with 0.5 M HCl to pH˜2. The organic layer was washed withH₂O (15.0 mL×3), then the solid NaHCO₃ was added to the combined aqueousphase until pH was reached to 8, after that, the aqueous phase wasextracted with ethyl acetate (50.0 mL×3), the combined organic layer wasdried over Na₂SO₄, filtered and concentrated. The residue was purifiedby reverse phase flash HPLC (¹⁸C, 0.1% TFA in water, 0-50% MeCN). Theobtained product was adjusted with saturated aqueous NaHCO₃ to pH-8,then concentrated, the aqueous layer was extracted with EA (100.0 mL×3),the combined organic layer was dried over Na₂SO₄, filtered andconcentrated to givetert-butyl-(2S)-2-(cyanomethyl)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(300 mg, 467 μmol, 35% yield, 99% purity) as yellow oil. LCMS [ESI,M+1]: 630.

Step D:2-[(2S)-4-[2-[[(2S,4R)-4-Fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution oftert-butyl-(2S)-2-(cyanomethyl)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 318 μmol, 1.0 eq) in dioxane (1.5 mL) was added HCl/dioxane (4M, 2.0 mL, 25.0 eq) at 25° C. The mixture was stirred at 25° C. for 1hour. After completion, the reaction mixture was quenched by additionsaturated aqueous NaHCO₃ (6.0 mL) at 0° C., and then diluted with H₂O10.0 mL and extracted with EA (15.0 mL×3). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated under reduced pressureto give2-[(2S)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(150 mg, crude) as yellow oil. The product was used into the next stepwithout further purification. LCMS [ESI, M+1]: 530.

Step E:2-[(2S)-4-[2-[[(2S,4R)-4-Fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(150 mg, 283 μmol, 1.0 eq) in ethyl acetate (1.0 mL) was added asolution of 2-fluoroprop-2-enoic acid (42.9 mg, 476 μmol, 1.68 eq) inethyl acetate (0.5 mL), then was added TEA (1.93 g, 19 mmol, 2.65 mL,67.0 eq) and T3P (455 mg, 715 μmol, 425 μL, 50% purity, 2.5 eq) and themixture was stirred at 0° C., after that the reaction mixture was warmedto 20° C. and stirred for 1 hours. After completion, the reactionmixture was quenched by addition H₂O 10.0 mL, and then extracted withethyl acetate (15.0 mL×3). The combined organic layers were dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by prep-HPLC (column: PhenomenexGemini 150*25 mm*10 μm; mobile phase: [water (0.05% ammonium hydroxidev/v)-MeCN]; B %: 58%-88%, 11.5 min) and lyophilization to give titlecompound2-[(2S)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile(50.1 mg, 82.9 μmol, two steps 26% yield, 99.5% purity) as a whitesolid. LCMS [ESI, M+1]: 602.

¹H NMR (400 MHz, Chloroform-d) δ 7.72 (d, J=8.4 Hz, 1H), 7.67 (t, J=8.0Hz, 1H), 7.46-7.43 (m, 2H), 7.26-7.21 (m, 2H), 5.50-5.38 (m, 1H),5.30-5.11 (m, 2H), 4.89 (br s, 1H), 4.45-4.40 (m, 1H), 4.30-4.20 (m,2H), 4.19-4.13 (m, 1H), 4.10-4.05 (m, 1H), 3.92-3.88 (m, 1H), 3.82-3.77(m, 1H), 3.62-3.46 (m, 3H), 3.25-3.18 (m, 2H), 3.15-3.09 (m, 1H),3.08-2.98 (m, 2H), 2.94 (s, 3H), 2.90-2.77 (m, 2H), 2.67-2.56 (m, 2H),2.51 (d, J=4.8 Hz, 3H), 2.38-2.27 (m, 1H), 2.07-1.89 (m, 1H).

Example 561

2-[(2S)-1-(2-Fluoroprop-2-enoyl)-4-[2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

1-tert-Butyl-2-methyl (2S4R)-4-methoxypyrrolidine-1,2-dicarboxylate. Tothe solution of(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (2g, 8.65 mmol, 1 eq) and Ag₂O (6.01 g, 26.0 mmol, 3 eq) in MeCN (40 mL)was added CH₃I (10.0 g, 70.8 mmol, 4.41 mL, 8.19 eq), the mixture wasstirred at 30° C. for 14 hours. To the mixture was added CH₃] (13.2 g,93.1 mmol, 5.80 mL, 10.8 eq), the mixture was stirred at 30° C. for 6hours. The reaction mixture was filtered, the filtrate was concentratedunder vacuum. The residue was purified by silica gel chromatography(PE:EtOAc=20:1-10.1) to give 1-tert-butyl-2-methyl(2S,4R)-4-methoxypyrrolidine-1,2-dicarboxylate (1.85 g, 6.99 mmol, 81%yield, 98% purity) as a yellow oil.

[(2S,4R)-4-Methoxy-1-methyl-pyrrolidin-2-yl]methanol. To the solution ofO1-tert-butyl O2-methyl (2S,4R)-4-methoxypyrrolidine-1,2-dicarboxylate(1.85 g, 7.13 mmol, 1 eq) in THF (50 mL) was added LiAlH₄ (542 mg, 14.3mmol, 2 eq) at 0° C., the mixture was stirred at 0° C. for 0.5 hour.Then the mixture was heated to 70° C. and stirred for 3 hours. ThenLiAlH₄ (542 mg, 14.27 mmol, 2 eq) was added at 10° C., the mixture washeated to 80° C. and stirred for 6 hours. The reaction mixture wasquenched by saturated Na₂SO₄ (5 mL), then filtered. The filter cake waswashed with THF (3×30 mL). The filtrate was concentrated under vacuum togive [(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]nethanol (840 mg, 5.21mmol, 73% yield, 90% purity) as a yellow oil which was used for nextstep without further purification.

¹H NMR (400 MHz, chloroform-d) δ=3.93-3.83 (m, 1H), 3.68 (dd, J=3.2,11.2 Hz, 1H), 3.48-3.36 (m, 2H), 3.30 (s, 3H), 2.67-2.58 (m, 1H),2.40-2.30 (m, 4H), 2.08 (td, J=8.0, 13.2 Hz, 1H), 1.90-1.79 (m, 1H).

Step A: Benzyl4-[(3S)-4-tert-butoxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate.To the solution of [(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methanol(367 mg, 2.52 mmol, 2 eq) in toluene (18 mL) was added t-BuONa (364 mg,3.79 mmol, 3 eq) at 0° C., then benzyl4-[(3S)-4-tert-butoxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(700 mg, 1.26 mmol, 1 eq) was added at 0° C., the reaction mixture wasstirred at 8° C. for 1 hour. Water (30 mL) was added into the mixture.The mixture was diluted with EtOAc (10 mL) and extracted with EtOAc(2×30 mL). The combined organic layers were washed with brine (20 mL).The combined organic layers were dried over anhydrous Na₂SO₄, filteredand concentrated under vacuum. The residue was purified by reverse phaseflash column (MeCN/Water (0.1% FA)=30%) to give benzyl4-[(3S)-4-tert-butoxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(450 mg, 694 μmol, 55% yield. 98% purity) as a yellow solid. LCMS [ESI,M+1]: 636.

Step B:tert-Butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To the solution of benzyl4-[(3S)-4-tert-butoxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(490 mg, 771 μmol, 1 eq) and NH₃·MeOH (5 mL, 25% purity) in MeOH (5 mL)was added Pd/C (100 mg, 10% purity) under N₂. The suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred under H₂ (15 psi) at 15° C. for 1 hour. The reaction mixture wasfiltered, the filter cake was washed with MeOH (3×5 mL). The filtratewas concentrated under vacuum to givetert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(360 mg, 682 μmol, 88% yield, 95% purity) as a yellow solid which wasused for next step without further purification.

Step C:tert-Butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To the solution of tert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(360 mg, 718 μmol, 1 eq), 1-bromo-8-methyl-naphthalene (238 mg, 1.08mmol, 1.5 eq), Cs₂CO₃ (701 mg, 2.15 mmol, 3 eq) and Xantphos (83.0 mg,143 μmol, 0.2 eq) in toluene (8 mL) was added Pd₂(dba)₃ (65.7 mg, 71.8μmol, 0.1 eq) under N₂. The suspension was degassed under vacuum andpurged with N₂ several times. The mixture was stirred under N₂ at 90° C.for 12 hours. The reaction mixture was filtered, the filtrate wasconcentrated under vacuum. The residue was purified by silica gelchromatography (from PE:EtOAc=5:1-1:1 to EtOAc:MeOH=1:0-20:1). Then theresidue was purified by reverse phase flash column (ACN/Water (0.1%FA)=45%) to givetert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(280 mg, 414 μmol, 58% yield. 95% purity) as a brown solid LCMS [ESI,M+1]: 642.

¹H NMR (400 MHz, chloroform-d) δ=7.74-7.60 (m, 2H), 7.45-7.37 (m, 1H),7.34 (t, J=7.6 Hz, 1H), 7.27-7.17 (m, 2H), 4.61 (br s, 1H), 4.39 (ddd,J=4.8, 6.8, 11.2 Hz, 1H), 4.30-4.20 (m, 1H), 4.16-4.11 (m, 1H),4.11-3.89 (m, 4H), 3.88-3.68 (m, 1H), 3.56-3.47 (m, 1H), 3.46-3.32 (m,2H), 3.30 (d, J=2.4 Hz, 3H), 3.21-3.05 (m, 3H), 3.01-2.85 (m, 5H),2.81-2.67 (m, 2H), 2.65-2.54 (m, 1H), 2.46 (d, J=4.0 Hz, 3H), 2.35-2.26(m, 1H), 2.11-2.05 (m, 1H), 2.00-1.88 (m, 1H), 1.52 (s, 9H).

Step D:2-[(2S)-4-[2-[[(2S,4R)-4-Methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To the solution of tert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(280 mg, 436 μmol, 1 eq) in dioxane (1 mL) was added HCl/dioxane (4 M,1.64 mL, 15 eq) was stirred at 10° C. for 1 hour. The reaction mixturewas concentrated under vacuum. The mixture was basified with saturatedNaHCO₃ to PH=8˜9 and extracted with EtOAc (3×15 mL). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum to give2-[(2S)-4-[2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(210 mg, 349 μmol, 80% yield, 90% purity) as a yellow solid which wasused for next step without further purification. LCMS [ESI, M+1]: 542.

Step E:2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To the solution of2-[(2S)-4-[2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(100 mg, 185 μmol, 1 eq), 2-fluoroprop-2-enoic acid (33.2 mg, 369 μmol,2 eq) and TEA (149 mg, 1.48 mmol, 206 μL, 8 eq) in EtOAc (2 mL) wasadded T3P (352 mg, 554 μmol, 329 μL, 50% purity, 3 eq) at 0° C., themixture was stirred at 10° C. for 0.5 hour. Water (3 mL) was added intothe mixture. The mixture was extracted with EtOAc (2×3 mL). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by prep-HPLC(column: Xtimate C18 150*25 mm*5 μm; mobile phase: [water (0.05%ammonium hydroxide v/v)-ACN]; B %: 52%-82%, 12 min) to give titlecompound2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(28.1 mg, 45.5 μmol, 25% yield, 99.4% purity) as a white solid. LCMS[ESI, M+1]: 614.

¹H NMR (400 MHz, chloroform-d) δ=7.65-7.54 (m, 2H), 7.38-7.30 (m, 1H),7.27 (t, J=7.6 Hz, 1H), 7.19-7.10 (m, 2H), 5.46-5.26 (m, 1H), 5.18 (brdd, J=3.6, 16.8 Hz, 1H), 4.83 (br s, 1H), 4.37-4.27 (m, 1H), 4.23-3.94(m, 4H), 3.92-3.85 (m, 1H), 3.84-3.76 (m, 1H), 3.70 (br d, J=18.0 Hz,1H), 3.46 (br d, J=8.8 Hz, 1H), 3.42-3.31 (m, 2H), 3.22 (d, J=2.0 Hz,3H), 3.18-3.07 (m, 2H), 3.06-2.87 (m, 2H), 2.87-2.64 (m, 6H), 2.59-2.49(m, 1H), 2.38 (d, J=4.4 Hz, 3H), 2.24 (ddd, J=3.2, 6.0, 9.6 Hz, 1H),2.04-1.94 (m, 1H), 1.93-1.81 (m, 1H).

Example 562

2-[(2S)-1-(2-Fluoroprop-2-enoyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

[(3R)-1-Methylpyrrolidin-3-yl]methanol. To the solution of tert-butyl(3R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (0.5 g, 2.48 mmol, 1 eq)in THF (20 mL) was added LiAlH₄ (189 mg, 4.97 mmol, 2 eq) at 0° C., thenthe mixture was warmed to 70° C. and stirred at 70° C. for 0.5 hour.Upon completion, the reaction mixture was quenched with saturated Na₂SO₄(1 mL). The precipitate was filtered off and the filter cake was washedwith THF (3×20 mL). The combined organic layers were dried over Na₂SO₄and concentrated under vacuum to give[(3R)-1-methylpyrrolidin-3-yl]methanol (220 mg, 1.72 mmol, 69% yield,90% purity) as a colorless oil which was used directly in the next stepwithout further purification.

1H NMR (400 MHz, chloroform-d) δ=3.67-3.57 (m, 1H), 3.50 (dd, J=6.0,10.0 Hz, 1H), 3.45-3.18 (m, 1H), 2.70 (dt, J=4.8, 8.8 Hz, 1H), 2.56-2.44(m, 2H), 2.42-2.24 (m, 5H), 2.04-1.90 (m, 1H), 1.68-1.54 (m, 1H).

Step A: Benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of benzyl (2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 841 μmol, 1 eq) and [(3R)-1-methylpyrrolidin-3-yl]methanol (194mg, 1.68 mmol, 2 eq) in toluene (10 mL) was added t-BuONa (162 mg, 1.68mmol, 2 eq). The mixture was stirred at 0° C. for 10 minutes. Uponcompletion, the mixture was diluted with water (10 mL) and extractedwith EtOAc (2×40 mL). The organic layers were dried over Na₂SO₄ andconcentrated under vacuum. The residue was purified by silica gelchromatography (EtOAc/MeOH 50/1 to 3/1) to give benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(290 mg, 427 μmol, 51% yield, 95% purity) as a yellow solid. LCMS [ESI,M+1]: 646.

¹H NMR (400 MHz, chloroform-d) δ=7.72-7.61 (m, 2H), 7.45-7.37 (m, 5H),7.37-7.30 (m, 2H), 7.27-7.16 (m, 2H), 5.28-5.15 (m, 2H), 4.68 (br s,1H), 4.30-4.01 (m, 6H), 4.00-3.73 (m, 2H), 3.56-3.31 (m, 2H), 3.26-3.06(m, 3H), 3.05-2.94 (m, 2H), 2.91 (s, 3H), 2.82-2.70 (m, 4H), 2.70-2.57(m, 2H), 2.47 (d, J=4.4 Hz, 3H), 2.20-2.07 (m, 1H), 1.80-1.67 (m, 1H).

Step B:2-[(2S)-4-[7-(8-Methyl-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(290 mg, 449 μmol, 1 eq) in MeOH (4 mL) was added NH₃·MeOH (2 mL, 15%purity), Pd/C (100 mg, 449 μmol, 10% purity, 1 eq) under N₂. Thesuspension was degassed under vacuum and purged with H₂ several times.The mixture was stirred under H₂ (15 psi) at 15° C. for 1 hour. Uponcompletion, the mixture was filtered and the filtrate was concentratedunder vacuum to give2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(150 mg, 279 μmol, 62% yield, 95% purity) as a yellow solid which wasused directly in the next step without further purification. LCMS [ESI,M+1]: 512.

Step C:2-[(2S)-1-(2-Fluoroprop-2-enoyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(120 mg, 235 μmol, 1 eq), 2-fluoroprop-2-enoic acid (42.2 mg, 469 μmol,2 eq) and TEA (71.2 mg, 704 μmol, 97.9 μL, 3 eq) in DMF (2 mL) was addedT3P (224 mg, 352 μmol, 209 μL, 50% purity in EtOAc, 1.5 eq) at −40° C.Then the mixture was stirred at −40° C. for 0.5 hour. Upon completion,the mixture was diluted with water (2 mL) and extracted with the mixedsolvent (EtOAc/MeOH 10/1, 5×5 mL). The organic layers were dried overNa₂SO₄ and concentrated under vacuum. The residue was purified bychromatography (Al₂O₃, EtOAc/MeOH 50/1 to 20/1) followed by prep-HPLC(column: Phenomenex Gemini 150*25 mm*10 μm; mobile phase: [water (10 mMNH₄HCO₃)-ACN], B %: 50%-100%, 10 min). The desired fractions werecollected and lyophilized to give title compound2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(16.0 mg, 26.5 μmol, 11% yield, 96.5% purity) as off-white solid. LCMS[ESI, M+1]: 584.

¹H NMR (400 MHz, chloroform-d) δ=7.74-7.61 (m, 2H), 7.45-7.38 (m, 1H),7.35 (t, J=7.6 Hz, 1H), 7.27-7.17 (m, 2H), 5.55-5.32 (m, 1H), 5.26 (dd,J=3.6, 16.8 Hz, 1H), 4.88 (br s, 1H), 4.33-4.02 (m, 5H), 4.01-3.65 (m,2H), 3.61-3.36 (m, 2H), 3.27-2.97 (m, 4H), 2.92 (s, 3H), 2.90-2.74 (m,2H), 2.74-2.56 (m, 4H), 2.55-2.42 (m, 2H), 2.36 (d, J=2.4 Hz, 3H),2.14-1.99 (m, 1H), 1.66-1.52 (m, 1H).

Example 563

2-[(2S)-1-[(E)-4-Fluorobut-2-enoyl]-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

2-[(2S)-1-[(E)-4-Fluorobut-2-enoyl]-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(260 mg, 508 μmol, 1.0 eq) in ethyl acetate (1.5 mL) was added asolution of (E)-4-fluorobut-2-enoic acid (106 mg, 1.02 mmol, 2.0 eq) inethyl acetate (0.5 mL), TEA (206 mg, 2.03 mmol, 283 μL, 4.0 eq) and T3P(647 mg, 1.02 mmol, 605 μL, 50% purity, 2.0 eq), and the mixture wasstirred at −40° C. and stirred for 1 hour. Ater completion, the reactionmixture was quenched by H2O (10.0 mL), and extracted with ethyl acetate(3×15.0 mL). The combined organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by prep-HPLC (column: Luna C18 150*25 5 u; mobilephase: [water (0.225% FA)-ACN]; B %: 25%-45%, 7.8 min). The obtainedproduct was adjusted to pH˜8 with saturated aqueous NaHCO₃, thenconcentrated, the aqueous layer was extracted with ethyl acetate (3×20.0mL), the combined organic layer was dried over Na2SO4, filtered andconcentrated to give title compound2-[(2S)-1-[(E)-4-fluorobut-2-enoyl]-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(132 mg, 220 μmol, 43% yield, 99% purity) as a white solid. LCMS [ESI,M+1]: 598.

¹H NMR (400 MHz, Chloroform-d) δ 7.70-7.62 (m, 2H), 7.43-7.38 (m, 1H),7.36-7.31 (m, 1H), 7.26-7.19 (m, 2H), 7.04-6.94 (m, 1H), 6.59 (d, J=14.4Hz, 1H), 5.17-4.60 (m, 3H), 4.41-4.35 (m, 1H), 4.28-3.44 (m, 9H),3.20-3.08 (m, 4H), 3.05-2.99 (m, 1H), 2.92 (s, 3H), 2.83-2.77 (m, 1H),2.72-2.62 (m, 2H), 2.47 (d, J=4.8 Hz, 3H), 2.32-2.25 (m, 1H), 2.09-2.01(m, 1H), 1.88-1.70 (m, 3H).

Example 564

2-[(2S)-4-[7-(8-Chloro-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile

Step A: Benzyl4-[(3S)-4-tert-butoxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate.To a solution of benzyl4-[(3S)-4-tert-butoxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(800 mg, 1.44 mmol, 1 eq) in toluene (20 mL) was added t-BuONa (277 mg,2.88 mmol, 2 eq) and3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propan-1-ol (340 mg,2.16 mmol, 1.5 eq) at 0° C. The mixture was stirred at 0° C. for 0.5hour. The reaction mixture was diluted with water (30 mL) and extractedwith ethyl acetate (30 mL×3). The combined organic layers were washedwith brine (20 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by reversephase flash [water (0.1% formic acid)/acetonitrile)]. The mixture wasadjusted pH=7 with saturated aqueous NaHCO₃ and extracted with ethylacetate (20 mL×3). The combined organic layers were washed with brine(20 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give the product. Benzyl4-[(3S)-4-tert-butoxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(500 mg, 725 μmol, 50% yield, 94% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 648.

¹H NMR (400 MHz, chloroform-d) δ=7.44-7.30 (m, 5H), 5.19 (s, 2H),4.79-4.53 (m, 2H), 4.51-4.30 (m, 41H), 4.09-3.71 (m, 5H), 3.67-3.58 (m,1H), 3.54-3.36 (m, 2H), 3.32-3.12 (m, 2H), 3.04-2.87 (m, 2H), 2.85-2.46(m, 7H), 2.00-1.89 (m, 2H), 1.85 (d, J=9.2 Hz, 1H), 1.72 (d, J=9.2 Hz,1H), 1.51 (s, 9H).

Step B: tert-Butyl(2S)-2-(cyanomethyl)-4-[2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of benzyl4-[(3S)-4-tert-butoxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(900 mg, 1.39 mmol, 1 eq) in MeOH (30 mL) was added Pd/C (100 mg, 10%purity) and NH₃·MeOH (20 mL, 25% purity) under N₂. The suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred under H₂ (15 psi) at 20° C. for 1 hour. The catalyst wasfiltered off and the filtrate was concentrated under vacuum. tert-butyl(2S)-2-(cyanomethyl)-4-[2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(650 mg, 1.06 mmol, 77% yield, 84% purity) was obtained as a yellowsolid and used to next step without purification. LCMS [ESI, M+1]: 514.

Step C: tert-Butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.To the solution of tert-butyl(2S)-2-(cyanomethyl)-4-[2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(180 mg, 350 μmol, 1 eq), 1-bromo-8-chloro-naphthalene (127 mg, 526μmol, 1.5 eq), Cs₂CO₃ (342 mg, 1.05 mmol, 3 eq) and RuPhos (65.4 mg, 140μmol, 0.4 eq) in toluene (6 mL) was added Pd₂(dba)₃ (64.2 mg, 70.1 μmol,0.2 eq) under N₂. The suspension was degassed under vacuum and purgedwith N₂ several times. The mixture was stirred under N₂ at 90° C. for 10hours. The reaction mixture was filtered, and the filtrate wasconcentrated under vacuum. The residue was purified by silica gelchromatography (from PE:EtOAc=5:1˜1:1 to EtOAc:MeOH=1:0˜20:1) to givetert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(130 mg, 173 μmol, 50% yield, 90% purity) as a brown solid. LCMS [ESI,M+1]: 674.

Step D:2-[(2S)-4-[7-(8-Chloro-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To the solution of tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(150 mg, 222 μmol, 1 eq) in dioxane (0.6 mL) was added HCl/dioxane (4 M,556 μL, 10 eq), the mixture was stirred at 10° C. for 1 hour. Thereaction mixture was concentrated under vacuum. The residue wasdissolved with water (15 mL) and EtOAc (10 mL), then separated. Theaqueous phase was basified by NaHCO₃ solid to PH=8˜9 and extracted withEtOAc (2×15 mL). The combined organic layers were washed with brine (20mL). The combined organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated under vacuum to give2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(100 mg, 162 μmol, 73% yield, 93% purity) as a brown solid which wasused for next step without further purification. LCMS [ESI, M+1]: 574.

Step E:2-[(2S)-4-[7-(8-Chloro-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.To the solution of2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(100 mg, 174 μmol, 1 eq), 2-fluoroprop-2-enoic acid (31.4 mg, 348 μmol,2 eq) and TEA (141 mg, 1.39 mmol, 194 μL, 8 eq) in EtOAc (2 mL) wasadded T3P (332 mg, 522 μmol, 311 μL, 50% purity, 3 eq) at 0° C., themixture was stirred at 10° C. for 0.5 hour. Water (3 mL) was added intothe mixture. The mixture was extracted with EtOAc (2×3 mL). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by prep-HPLC(column: Xtimate C18 10μ 250 mm*50 mm; mobile phase: [water (0.05%ammonium hydroxide v/v)-ACN]; B %: 45%-75%, 12 min) to give titlecompound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile(26.5 mg, 41 μmol, 24% yield, 99.9% purity) as a white solid. LCMS [ESI,M+1]: 646.

¹H NMR (400 MHz, chloroform-d) δ=7.76 (d, J=8.4 Hz, 1H), 7.62 (t, J=7.2Hz, 1H), 7.53 (d, J=7.2 Hz, 1H), 7.45 (td, J=7.6, 12.4 Hz, 1H), 7.34 (t,J=7.6 Hz, 1H), 7.26-7.18 (m, 1H), 5.53-5.32 (m, 1H), 5.25 (dd, J=3.6,16.8 Hz, 1H), 5.12-4.64 (m, 1H), 4.49-4.31 (m, 4H), 4.21-3.98 (m, 3H),3.95-3.76 (m, 2H), 3.68-3.55 (m, 2H), 3.52-3.36 (m, 2H), 3.33-2.97 (m,4H), 2.95-2.66 (m, 5H), 2.64-2.49 (m, 2H), 1.93 (m, 2H), 1.84 (br d,J=8.4 Hz, 1H), 1.71 (br d, J=10.0 Hz, 1H).

Example 565

2-[(2S)-1-[(E)-4-Fluorobut-2-enoyl]-4-[7-(8-methyl-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

Step A: tert-Butyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.A mixture of tert-butyl(2S)-2-(cyanomethyl)-4-[2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(350 mg, 681 μmol, 1 eq), 1-bromo-8-methyl-naphthalene (226 mg, 1.02mmol, 1.5 eq), Xantphos (78.9 mg, 136 μmol, 0.2 eq), Pd₂(dba)₃ (62.4 mg,68.1 μmol, 0.1 eq) and Cs₂CO₃ (555 mg, 1.70 mmol, 2.5 eq) in toluene (10mL) was degassed and purged with N₂ for 3 times, and then the mixturewas stirred at 90° C. for 12 hours under N₂. The reaction mixture wasdiluted with water (20 mL) and extracted with ethyl acetate (20 mL×3).The combined organic layers were washed with brine (20 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (SiO₂, ethylacetate/methanol=300/1 to 10/1) tert-butyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(270 mg, 379 μmol, 56% yield, 92% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 654.

¹H NMR (400 MHz, chloroform-d) δ=7.75-7.61 (m, 2H), 7.45-7.37 (m, 1H),7.34 (t, J=7.2 Hz, 1H), 7.26-7.15 (m, 2H), 4.62 (br s, 1H), 4.45-4.31(m, 3H), 4.30-4.16 (m, 1H), 4.10-3.70 (m, 5H), 3.61 (br d, J=7.6 Hz,1H), 3.57-3.44 (m, 2H), 3.43-3.25 (m, 1H), 3.24-3.05 (m, 3H), 3.03-2.86(m, 5H), 2.84-2.67 (m, 4H), 2.66-2.48 (m, 2H), 2.00-1.88 (m, 2H), 1.84(d, J=9.6 Hz, 1H), 1.72 (d, J=9.6 Hz, 1H), 1.52 (s, 9H).

Step B:2-[(2S)-4-[7-(8-Methyl-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(250 mg, 382 μmol, 1 eq) in dioxane (2 mL) was added HCl/dioxane (4 M,1.91 mL, 1.00 eq) at 0° C. The mixture was stirred at 0° C. for 1 hour.The reaction mixture was concentrated under vacuum. The residue wasdiluted with water (20 mL), and then the mixture was adjusted pH=7 withsaturated NaHCO₃ aqueous solution and extracted with ethyl acetate (20mL×3). The combined organic layers were washed with brine (20 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to givethe product.2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(260 mg, crude) was obtained as a yellow oil and used to next stepwithout purification. LCMS [EST, M+1]: 554.

Step C:2-[(2S)-1-[(E)-4-Fluorobut-2-enoyl]-4-[7-(8-methyl-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(120 mg, 216 μmol, 1 eq), TEA (87.7 mg, 866 μmol, 121 μL, 4 eq) and(E)-4-fluorobut-2-enoic acid (45.1 mg, 433 μmol, 2 eq) in ethyl acetate(2 mL) was added T3P (276 mg, 433 μmol. 258 μL, 50% purity, 2 eq) at−70° C. The mixture was stirred at −70° C. for 0.5 hour. The reactionmixture was quenched with diluted with HCl (1 N, 1 mL) and then dilutedwith water (20 mL). The mixture was extracted with ethyl acetate (20mL×3). The combined organic layers were washed with brine (10 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by prep-HPLC (column: Waters Xbridge150*25 5μ, mobile phase: [water (0.05% ammonium hydroxide v/v)-ACN], B%: 40%-70%, 10 min). The desired fractions were collected andlyophilized. Title compound2-[(2S)-1-[(E)-4-fluorobut-2-enoyl]-4-[7-(8-methyl-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(14.5 mg, 22.5 μmol, 10% yield, 99.3% purity) was obtained as a whitesolid. LCMS [ESI, M+1]: 640.

¹H NMR (400 MHz, chloroform-d) δ=7.70 (d, J=8.4 Hz, 1H), 7.65 (t, J=8.0Hz, 1H), 7.45-7.30 (m, 2H), 7.27-7.16 (m, 2H), 7.09-6.91 (m, 1H), 6.59(d, J=15.2 Hz, 1H), 5.29-4.48 (m, 3H), 4.44-4.31 (m, 3H), 4.29-3.72 (m,6H), 3.71-3.40 (m, 4H), 3.28-2.96 (m, 4H), 2.95-2.88 (m, 4H), 2.87-2.56(m, 5H), 2.52 (d, J=10.0 Hz, 1H), 1.99-1.87 (m, 2H), 1.84 (d, J=9.6 Hz,1H), 1.71 (d, J=9.6 Hz, 1H).

Example 566

2-[(2S)-1-(2-Fluoroprop-2-enoyl)-4-[7-(8-methyl-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

2-[(2S)-1-(2-Fluoroprop-2-enoyl)-4-[7-(8-methyl-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(100 mg, 181 μmol, 1 eq) and 2-fluoroprop-2-enoic acid (32.5 mg, 361μmol, 2 eq) in DCM (1 mL) was added HATU (137 mg, 361 μmol, 2 eq) andDIEA (93.4 mg, 722 μmol, 126 μL, 4 eq). After stirred at 0° C. for 0.5hour, the reaction mixture was diluted with water (10 mL) and extractedwith ethyl acetate (10 mL×3). The combined organic layers were washedwith brine (10 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by TLC(DCM/MeOH=10/1) and further purified by prep-HPLC (column: Xtimate C1810μ 250 mm*50 mm; mobile phase: [water (0.05% ammonium hydroxidev/v)-ACN]; B %: 45%-75%, 12 min). The desired fraction was collected andlyophilized. Title compound2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[7-(8-methyl-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(12 mg, 19.1 μmol, 11% yield, 99.6% purity) was obtained as a whitesolid. LCMS [ESI, M+1]: 626.

¹H NMR (400 MHz, chloroform-d) δ=7.63 (d, J=8.0 Hz, 1H), 7.58 (t, J=8.4Hz, 1H), 7.39-7.23 (m, 2H), 7.19-7.09 (m, 2H), 5.35 (d, J=48.8 Hz, 1H),5.18 (dd, J=3.6, 16.8 Hz, 1H), 5.04-4.40 (m, 1H), 4.37-3.89 (m, 7H),3.86-3.61 (m, 2H), 3.59-3.32 (m, 4H), 3.20-2.40 (m, 14H), 1.95-1.81 (m,2H), 1.78 (d, J=9.6 Hz, 1H), 1.65 (d, J=9.6 Hz, 1H).

Example 567

2-[(2S)-1-(2-Fluoroprop-2-enoyl)-4-[7-[8-(hydroxymethyl)-1-naphthyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

8-Bromonaphthalene-1-carbaldehyde. To a solution of1,8-dibromonaphthalene (5 g, 17.5 mmol, 1 eq) in THF (100 mL) was addedn-BμLi (2.5 M, 9.09 mL, 1.3 eq) at −70° C. dropwise. After stirring for30 minutes at −70° C., DMF (12.8 g, 175 mmol, 13.5 mL, 10 eq) was addeddropwise. The mixture was warmed up to 12° C. and stirred for another0.5 hour. Upon completion, the mixture was quenched with saturatedaqueous NH₄Cl (20 mL). The separated aqueous phase was extracted withEtOAc (2×50 mL). The combined organic layers were dried over Na₂SO₄,filtered and concentrated under vacuum to give8-bromonaphthalene-1-carbaldehyde (4.5 g, crude) as a yellow solid whichwas used directly in the next step without further purification.

¹H NMR (400 MHz, chloroform-d) δ=11.4 (s, 1H), 8.04-7.92 (m, 2H), 7.90(d, J=8.0 Hz, 2H), 7.60-7.55 (m, 1H), 7.39 (t, J=8.0 Hz, 1H).

(8-Bromo-1-naphthyl)methanol. To a mixture of8-bromonaphthalene-1-carbaldehyde (4.5 g, 19.1 mmol) in MeOH (80 mL) wasadded NaBH₄ (2.90 g, 76.6 mmol) in one portion at 0° C. The mixture wasstirred at 0° C. for 30 minutes. Upon completion, to the mixture wasadded water (1 mL) and the mixture was concentrated under vacuum. Theresidue was diluted with water (10 mL) and extracted with EtOAc (2×40mL). The organic layers were dried over Na₂SO₄ and concentrated undervacuum. The residue was purified by silica gel chromatography (PE/EtOAc30/1 to 3/1) to give (8-bromo-1-naphthyl)methanol (3.3 g, 12.5 mmol, twosteps 72% yield, 90% purity) as a yellow solid.

¹H NMR (400 MHz, chloroform-d) δ=7.92-7.82 (m, 3H), 7.71 (d, J=6.8 Hz,1H), 7.49 (t, J=7.6 Hz, 1H), 7.32-7.27 (m, 1H), 5.48 (br s, 2H).

2-[(8-Bromo-1-naphthyl)methoxy]tetrahydropyan. To a solution of(8-bromo-1-naphthyl)methanol (0.5 g, 2.11 mmol, 1 eq) in DCM (10 mL) wasadded DHP (355 mg, 4.22 mmol, 386 μL, 2 eq), followed by TsOH·H₂O (40.1mg, 211 μmol, 0.1 eq) at 12° C. The mixture was stirred at 12° C. for 2hours. Upon completion, the mixture was quenched with saturated aqueousNaHCO₃ solution (2 mL) and diluted with water (5 mL). The separatedaqueous phase was extracted with EtOAc (10 mL). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated under vacuum.The residue was purified by silica gel chromatography (PE/EtOAc 500/1 to100/1) to give 2-[(8-bromo-1-naphthyl)methoxy]tetrahydropyran (560 mg,1.57 mmol, 74% yield, 90% purity) as a colorless oil.

¹H NMR (400 MHz, chloroform-d) δ=7.94-7.88 (m, 2H), 7.85 (t, J=8.4 Hz,2H), 7.56-7.50 (m, 1H), 7.36-7.28 (m, 1H), 5.63 (s, 2H), 4.92 (t, J=3.6Hz, 1H), 4.07-3.97 (m, 1H), 3.69-3.61 (m, 1H), 2.08-1.76 (m, 4H),1.75-1.65 (m, 2H).

Step A: Benzyl(2S)-2-(cyanomethyl)-4-(2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[8-(tetrahydropyran-2-yloxymethyl)-1-naphthyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.2-[(8-bromo-1-naphthyl)methoxy]tetrahydropyran (476 mg, 1.48 mmol, 1.5eq), benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 989 μmol, 1 eq), Cs2CO3 (806 mg, 2.47 mmol, 2.5 eq),(5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (229mg, 396 μmol, 0.4 eq) and Pd2(dba)3 (181 mg, 198 μmol, 0.2 eq) intoluene (20 mL) was de-gassed and then heated to 90° C. for 10 hoursunder N2. Upon completion, the mixture was filtered through a pad ofcelite and the filtrate was concentrated under vacuum. The residue waspurified by reverse phase flash [water (0.1% FA)/acetonitrile]. Thedesired fractions were collected, neutralized with saturated aqueousNaHCO₃, concentrated under vacuum to remove MeCN and extracted withEtOAc (2×30 mL). The organic layers were dried over Na₂SO₄ andconcentrated under vacuum to give benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[8-(tetrahydropyran-2-yloxymethyl)-1-naphthyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(280 mg, 338 μmol, 34% yield, 90% purity) as a yellow solid. LCMS [ESI,M+1]: 746.

Step B:2-[(2S)-4-[2-[[(2S)-1-Methylpyrrolidin-2-yl]methoxy]-7-[8-(tetrahydropyran-2-yloxymethyl)-1-naphthyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[8-(tetrahydropyran-2-yloxymethyl)-1-naphthyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(280 mg, 375 μmol, 1 eq) in MeOH (6 mL) was added NH₃/MeOH (4 mL, 20%purity), Pd/C (120 mg, 10% purity) under N₂. The suspension was degassedunder vacuum and purged with H₂ for several times. The mixture wasstirred under H₂ (15 psi) at 15° C. for 1 hour. Upon completion, themixture was filtered through a pad of celite and the filtrate wasconcentrated under vacuum to give2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[8-(tetrahydropyran-2-yloxymethyl)-1-naphthyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(200 mg, 294 μmol. 78% yield, 90% purity) as a yellow solid which wasused directly in the next step without further purification. LCMS [ESI,M+1]: 612.

Step C:2-[(2S)-1-(2-Fluoroprop-2-enoyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[8-(tetrahydropyran-2-yloxymethyl)-1-naphthyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[8-(tetrahydropyran-2-yloxymethyl)-1-naphthyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(180 mg, 294 μmol, 1 eq), T3P (562 mg, 883 μmol, 525 μL, 50% purity inEtOAc, 3 eq) and TEA (238 mg, 2.35 mmol, 328 μL, 8 eq) in EtOAc (4 mL)was added 2-fluoroprop-2-enoic acid (53.0 mg, 588 μmol, 2 eq) at 0° C.The mixture was stirred at 15° C. for 0.5 hour. Upon completion, themixture was diluted with water (4 mL) and extracted with EtOAc (3×10mL). The organic layers were dried over Na₂SO₄ and concentrated undervacuum. The residue was purified by reverse phase flash [water (0.1%FA)/acetonitrile]. The desired fractions were collected and neutralizedwith NaHCO₃, concentrated under vacuum to remove MeCN and extracted withEtOAc (2×100 mL). The organic layers were dried over Na₂SO₄ andconcentrated under vacuum to give2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[8-(tetrahydropyran-2-yloxymethyl)-1-naphthyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(160 mg, 227 μmol, 77% yield, 97% purity) as a yellow solid. LCMS [ESI,M+1]: 684.

Step D:[(2S)-1-(2-Fluoroprop-2-enoyl)-4-[7-[8-(hydroxymethyl)-1-naphthyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[8-(tetrahydropyran-2-yloxymethyl)-1-naphthyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(150 mg, 219 μmol, 1 eq) in DCM (160 μL) was added TFA (250 mg, 2.19mmol, 162 μL, 10 eq). The mixture was stirred at 15° C. for 2 hours.Upon completion, the mixture was diluted with dichloromethane (3 mL) andadjusted pH=9 with saturated Na₂CO₃ aqueous solution. The separatedaqueous phase was extracted with DCM (5 mL). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated under vacuum. Theresidue was purified by prep-HPLC (column: Xtimate C18 150*25 mm*5 μm;mobile phase: [water (0.05% ammonium hydroxide v/v)-ACN]; B %: 42%-72%,8 min). The desired fractions were collected and lyophilized to givetitle compound2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[7-[8-(hydroxymethyl)-1-naphthyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(62.0 mg, 103 μmol, 47% yield, 100% purity) as a white solid. LCMS [ESI,M+1]: 600.

¹H NMR (400 MHz, chloroform-d) δ=7.84 (d, J=8.0 Hz, 1H), 7.79 (dd,J=3.2, 7.2 Hz, 1H), 7.55-7.44 (m, 3H), 7.44-7.38 (m, 1H), 5.55-5.32 (m,1H), 5.26 (dd, J=3.6, 16.8 Hz, 1H), 5.21-4.94 (m, 2H), 4.89 (br t,J=13.2 Hz, 1H), 4.41-3.90 (m, 7H), 3.66-3.39 (m, 2H), 3.37-3.00 (m, 5H),3.00-2.58 (m, 4H), 2.50-2.43 (m, 3H), 2.33-2.22 (m, 1H), 2.11-1.98 (m,1H), 1.90-1.73 (m, 3H).

Example 568

2-[(2S)-1-(2-Fluoroprop-2-enoyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

Step A: tert-Butyl4-[(3S)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate.To a mixture of tert-butyl2-methylsulfanyl-4-(trifluoromethylsulfonyloxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(20.0 g, 46.6 mmol, 1.00 eq) and benzyl(2S)-2-(cyanomethyl)piperazine-1-carboxylate (13.3 g, 51.2 mmol, 1.10eq) in DMAc (250 mL) was added DIEA (18.1 g, 140 mmol, 24.3 mL, 3 eq) inportion at 0° C. under N₂. The mixture was heated to 50° C. and stirredfor 1 hour. The reaction mixture was diluted with water (100 mL) andextracted with ethyl acetate (3×300 mL). The combined organic layerswere washed with water (3×500 mL), dried over sodium sulfate, filteredand concentrated under reduced pressure to give a residue. The residuewas purified by column chromatography (SiO₂, petroleum ether/ethylacetate=50/1 to 1/1). Compound tert-butyl4-[(3S)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(23.0 g, 42.7 mmol, 92% yield, 100% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 539.

Step B: Benzyl(2S)-2-(cyanomethyl)-4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate. To a mixture oftert-butyl4-[(3S)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(23.0 g, 42.7 mmol, 1.00 eq) in dioxane (200 mL) was added HCl/dioxane(4 M, 192 mL, 18.0 eq). After stirred at 20° C. and for 0.5 hour, thereaction mixture was filtered and the filter cake was dissolved in ethylacetate (200 mL). The pH was adjusted to 8-9 with saturated Na₂CO₃solution and then diluted with water (20.0 mL). The separated waterlayer was extracted with ethyl acetate (2×50 mL). The combined organiclayers were dried over sodium sulfate, filtered and concentrated underreduced pressure to give a residue. The residue was used into the nextstep directly without further purification. Compound benzyl(2S)-2-(cyanomethyl)-4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (16.1 g, 34.5 mmol, 81%yield, 94% purity) was obtained as a yellow solid.

¹H NMR (400 MHz, chloroform-d) δ=7.42-7.33 (m, 51H), 5.25-5.12 (m, 2H),4.66 (br s, 1H), 4.11-4.04 (m, 1H), 4.03-3.90 (m, 3H), 3.84 (br d,J=13.6 Hz, 1H), 3.34-3.17 (m, 2H), 3.11 (td, J=5.2, 10.4 Hz, 1H),3.04-2.93 (m, 2), 2.88-2.76 (m, 1H), 2.75-2.56 (m, 3H), 2.50 (s, 3H).

Step C: Benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a mixture of benzyl(2S)-2-(cyanomethyl)-4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(16.1 g, 36.7 mmol, 1.00 eq) and 1-bromo-8-methyl-naphthalene (10.6 g,47.7 mmol, 1.30 eq) in toluene (350 mL) was added Pd₂(dba)₃ (6.72 g,7.34 mmol, 0.20 eq), Xantphos (8.50 g, 14.7 mmol, 0.40 eq) and Cs₂CO₃(35.9 g, 110 mmol, 3.00 eq). The mixture was degassed and purged with N₂for 3 times. After stirred at 90° C. for 8 hours, the reaction mixturewas diluted with water (1×100 mL) and extracted with ethyl acetate(3×150 mL). The combined organic layers were washed with water (1×300mL) and brine (1×300 mL), dried over sodium sulfate, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by column chromatography (SiO₂, petroleum ether/ethylacetate=100/1 to 2/1) and concentrated under reduced pressure to give aresidue. Compound benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(15.3 g, 26.5 mmol, 72% yield) was obtained as a yellow solid.

¹H NMR (400 MHz, chloroform-d) δ=7.68-7.55 (m, 2H), 7.40-7.28 (m, 7H),7.22 (s, 2H), 5.22-5.09 (m, 2H), 4.64 (br s, 1H), 4.27-4.14 (m, 1H),4.05-3.84 (m, 2H), 3.83 3.68 (m, 1H), 3.55-3.30 (m, 2H), 3.18-3.03 (m,3H), 3.01-2.79 (m, 5H), 2.78-2.50 (m, 3H), 2.45 (d, J=4.8 Hz, 3H).

Step D: Benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a mixture of benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-t-naphthyl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(13.3 g, 23.0 mmol, 1.00 eq) in EtOAc (200 mL) was added m-CPBA (4.67 g,23.0 mmol, 85% purity, 1.00 eq) at 0° C. under N₂. After stirring at 0°C. for 30 min, the reaction mixture was quenched with saturated Na₂S₂O₃(100 mL) at 0° C. The separated organic layer was diluted with water(1×100 mL) and extracted with ethyl acetate (3×100 mL). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by column chromatography (SiO₂, petroleum ether/ethylacetate=50/1 to 0/1). Compound benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(9.60 g, 15.3 mmol, 67% yield, 95% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 595.

¹H NMR (400 MHz, chloroform-d) δ=7.74-7.63 (m, 2H), 7.47-7.31 (m, 7H),7.27-7.17 (m, 2H), 5.25-5.17 (m, 2H), 4.67 (br s, 1H), 4.48-4.21 (m,2H), 4.10-3.88 (m, 2H), 3.66-3.46 (m, 2H), 3.42-3.04 (m, 4H), 3.02-2.83(m, 6H), 2.81-2.60 (m, 1H), 2.81-2.60 (m, 3H).

Step E: tert-Butyl(2S)-4-[2-[[(2S)-1-tert-butoxycarbonylpyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.To a mixture of benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 841 μmol, 1.00 eq) and tert-butyl(2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (338 mg, 1.68 mmol, 2.00eq) in toluene (10.0 mL) was added t-BuONa (242 mg, 2.52 mmol, 3.00 eq)in portion at 0° C. under N₂. After stirring at 0° C. for 30 min, thereaction mixture was quenched by adding hydrochloric acid (1 M) 2 mL at0° C., and water (10 mL). The mixture was extracted with ethyl acetate(20 mL×3). The combined organic layers were washed with water (30 mL×1)and brine (30 mL×1), dried over sodium sulfate, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by column chromatography (SiO₂, petroleum ether/ethylacetate=50/1 to 0/1). Compound tert-butyl(2S)-4-[2-[[(2S)-1-tert-butoxycarbonylpyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(330 mg, 473 μmol, 56% yield) was obtained as a yellow solid.

¹H NMR (400 MHz, chloroform-d) δ=7.73-7.61 (m, 2H), 7.47-7.31 (m, 7H),7.26-7.15 (m, 2H), 5.27-5.14 (m, 2H), 4.68 (br s, 1H), 4.42-4.17 (m,3H), 4.07-3.73 (m, 3H), 3.58-3.29 (m, 5H), 3.25-2.88 (m, 8H), 2.86-2.51(m, 3H), 2.03-1.76 (m, 4H), 1.44 (d, J=4.8 Hz, 9H).

Step F: tert-Butyl(2S)-2-[[4-[(3S)-3-(cyanomethyl)piperazin-1-yl]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate.To a mixture of tert-butyl(2S)-4-[2-[[(2S)-1-tert-butoxycarbonylpyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(330 mg, 473 μmol, 1.00 eq) in MeOH (15 mL) was added NH₃·MeOH (15 mL,20% purity), Pd(OH)₂/C (80 mg, 20% purity) in one portion under N₂. Thesuspension was degassed under vacuum and purged with H₂ for three times.The mixture was stirred under H₂ (15 psi) at 20° C. for 1 hour. Thecatalyst was filtered off and the filtrate was concentrated underreduced pressure to give a residue. The crude product was used into thenext step directly without further purification. Compound tert-butyl(2S)-2-[[4-[(3S)-3-(cyanomethyl)piperazin-1-yl]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate(200 mg, 335 μmol, 71% yield) was obtained as a yellow solid. LCMS [ESI,M+1]: 598.

Step G: tert-Butyl(2S)-2-[[4-[(3S)-3-(cyanomethyl)-4-(2-fluoroprop-2-enoyl)piperazin-1-yl]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate.To a mixture of tert-butyl(2S)-2-[[4-[(3S)-3-(cyanomethyl)piperazin-1-yl]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate(190 mg, 318 μmol, 1.00 eq) and 2-fluoroprop-2-enoic acid (42.9 mg, 477μmol, 1.50 eq) in DCM (15.0 mL) was added DIEA (123 mg, 954 μmol, 166uL, 3.00 eq) and HATU (181 mg, 477 μmol, 1.50 eq) in one portion at 0°C. under N₂. After stirring at 0° C. for 30 min, the reaction mixturewas diluted with water (10 mL). The separated organic layer was washedwith brine (1×10 mL), dried over Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by column chromatography (SiO₂,DCM:MeOH=50:1 to 5:1). Compound tert-butyl(2S)-2-[[4-[(3S)-3-(cyanomethyl)-4-(2-fluoroprop-2-enoyl)piperazin-1-yl]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate(210 mg, 292 μmol, 92% yield, 93% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 670.

Step H:2-[(2S)-1-(2-Fluoroprop-2-enoyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a mixture of tert-butyl(2S)-2-[[4-[(3S)-3-(cyanomethyl)-4-(2-fluoroprop-2-enoyl)piperazin-1-yl]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate(210 mg, 314 μmol, 1.00 eq) in DCM (5.00 mL) was added TFA (1.07 g, 9.41mmol, 696 μL, 30.0 eq) in one portion at 20° C. under N₂. After stirredat 20° C. for 30 min, the reaction mixture was concentrated underreduced pressure to give a residue. The residue was purified byprep-HPLC (column: Phenomenex Synergi C18 150×30 mm×4 μm: mobile phase:[water (0.225% FA)-ACN]; B %: 20%-50%, 5 min). Title compound2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(75.5 mg, 122 μmol, 39% yield, 99.8% purity, FA) was obtained as aoff-white solid. LCMS [ESI, M+1]: 570.

¹H NMR (400 MHz, chloroform-d) δ=7.72-7.61 (m, 2H), 7.44-7.30 (m, 2H),7.27-7.14 (m, 2H), 6.49-5.98 (m, 1H), 5.55-5.32 (m, 1H), 5.25 (dd,J=3.6, 16.8 Hz, 1H), 4.58-4.42 (m, 2H), 4.36-3.87 (m, 5H), 3.86-3.67 (m,1H), 3.64-3.37 (m, 2H), 3.35-3.26 (m, 2H), 3.25-2.94 (m, 4H), 2.92-2.70(m, 5H), 2.66-2.51 (m, 1H), 2.18-1.81 (m, 4H).

Example 569

2-[(2S)-1-(2-Fluoroprop-2-enoyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methyl-5-oxo-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

(5S)-5-(tetrahydropyran-2-yloxymethyl)pyrrolidin-2-one. To a mixture of(5S)-5-(hydroxy methyl)pyrrolidin-2-one (5.00 g 43.4 mmol 1.00 eq) andDHP (3.65 g, 43.4 mmol, 3.97 mL, 1.00 eq) in DCM (80.0 mL) was addedTsOH·H₂O (826 mg, 4.34 mmol, 0.10 eq). The mixture was stirred at 15° C.for 12 hours. The reaction mixture was washed with brine (30.0 mL×1),dried over sodium sulfate, filtered and concentrated under reducedpressure to give a residue. The residue was purified by columnchromatography (SiO₂, petroleum ether/ethyl acetate 20/1 to 0:1).Compound (5S)-5-(tetrahydropyran-2-yloxymethyl)pyrrolidin-2-one (5.70 g,28.6 mmol, 66% yield) was obtained as a yellow oil.

¹H NMR (400 MHz, chloroform-d) δ=6.36-6.01 (m, 1H), 4.66-4.47 (m, 1H),3.92-3.71 (m, 2.5H), 3.64-3.43) (m, 2H), 3.24 (dd, J=8.0, 9.6 Hz, 0.5H),2.42-2.10 (m, 3H), 1.86-1.64 (m, 3H), 1.62-1.48 (m, 4H).

(5S)-1-Methyl-5-(tetrahydropyran-2-yloxymethyl)pyrrolidin-2-one. To amixture of (5S)-5-(tetrahydropyran-2-yloxymethyl)pyrrolidin-2-one (5.60g, 28.1 mmol, 1.00 eq) in DMF (60.0 mL) was added NaH (1.35 g, 33.7mmol, 60% purity, 1.20 eq) in portion at −40° C. under N₂. The mixturewas stirred at −40° C. for 30 min, then CH₃I (6.58 g, 46.4 mmol, 2.89mL, 1.65 eq) was added and stirred at 0° C. for 2.5 hours. The reactionmixture was quenched by adding saturated NaHSO₃ aqueous solution (30.0mL) and extracted with EA (3×50.0 mL). The combined organic phase wasdried over Na₂SO₄ and concentrated to dryness. The residue was purifiedby column chromatography (SiO₂, petroleum ether/ethyl acetate=10/1 to0/1). Compound(5S)-1-methyl-5-(tetrahydropyran-2-yloxymethyl)pyrrolidin-2-one (4.40 g20.6 mmol, 73% yield) was obtained as a yellow oil.

¹H NMR (400 MHz, chloroform-d) δ=4.59 (td, J=3.2, 13.6 Hz, 1H),3.93-3.73 (m, 2H), 3.63-3.71 (m, 1H), 3.57-3.44 (m, 2H), 2.88 (d, J=4.4Hz, 3H), 2.54-2.40 (m, 1H), 2.38-2.24 (m, 1H), 2.07-2.20 (m, 1H),1.93-1.53 (m, 7H).

(5S)-5-(Hydroxymethyl)-1-methyl-pyrrolidin-2-one. To a mixture of(5S)-1-methyl-5-(tetrahydropyran-2-yloxymethyl)pyrrolidin-2-one (2.20 g,10.3 mmol, 1.00 eq) in DCM (20.0 mL) was added TFA (23.5 g, 206 mmol,15.3 mL, 20.0 eq). The mixture was stirred at 15° C. for 30 min. Thereaction mixture was concentrated under reduced pressure to give aresidue. The crude product was used in the next step directly withoutfurther purification. Compound(5S)-5-(hydroxymethyl)-1-methyl-pyrrolidin-2-one (2.60 g, crude) wasobtained as a red oil.

Step A: Benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methyl-5-oxo-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a mixture of (5S)-5-(hydroxymethyl)-1-methyl-pyrrolidin-2-one (543mg, 4.20 mmol, 5.00 eq) in THF (30.0 mL) was added t-BuONa (808 mg, 8.41mmol, 10.0 eq) in portion at 0° C. under N₂. The mixture was stirred at0° C. for 30 min, then benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 841 μmol, 1.00 eq) was added and warmed to 15° C. and stirredfor 0.5 hour. The reaction mixture was diluted with water (20 mL) andextracted with ethyl acetate (30 mL×3). The combined organic layers werewashed with water (50 mL×1), dried over sodium sulfate, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by reverse phase flash [water (0.1% TFA)/acetonitrile]. Thedesired fractions were collected and neutralized with saturated NaHCO₃solution (10.0 mL) and extracted with ethyl acetate (50.0 mL×2). Theseparated organic layer was dried over sodium sulfate, filtered andconcentrated under vacuum Compound benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methyl-5-oxo-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(162 mg, 243 μmol, 29% yield, 99% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 660.

Step B:2-[(2S)-4-[7-(8-Methyl-1-naphthyl)-2-[[(2S)-1-methyl-5-oxo-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a mixture of benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methyl-5-oxo-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(130 mg, 197 μmol, 1.00 eq) in MeOH (2.00 mL) was added NH₃·MeOH (1.00mL, 20% purity) and Pd/C (35.0 mg, 10% purity). The suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred under H₂ (15 psi) at 15° C. for 1 hour. The reaction mixture wasfiltered and concentrated under reduced pressure to give a residue. Thecrude product was used in the next step directly without furtherpurification. Compound2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methyl-5-oxo-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(70.0 mg, crude) was obtained as a brown solid. LCMS [ESI, M+1]: 526.

Step C:2-[(2S)-1-(2-Fluoroprop-2-enoyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methyl-5-oxo-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a mixture of2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methyl-5-oxo-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(60.0 mg, 114 μmol, 1.00 eq) and 2-fluoroprop-2-enoic acid (20.6 mg, 228μmol, 2.00 eq) in EA (1.00 mL) was added TEA (92.4 mg, 913 μmol, 127 uL,8.00 eq), T3P (218 mg, 342 μmol, 204 uL, 50% purity, 3.00 eq) in portionat 0° C. under N₂. The mixture was stirred at 0° C. for 30 min. Thereaction mixture was diluted with water (5.00 mL) and extracted withethyl acetate (10.0 mL×3). The combined organic layers were washed withwater (10.0 mL×1) and brine (10.0 mL×1), dried over sodium sulfate,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by prep-HPLC (column: Xtimate C18 150×25 mm×5 um;mobile phase: [water (0.05% ammonium hydroxide v/v)-ACN]; B %: 42%-72%,10 min). Tide compound2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methyl-5-oxo-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(26.8 mg, 43.9 μmol, two steps 26% yield, 98% purity) was obtained as awhite solid. LCMS [ESI, M+1]: 598.

¹H NMR (400 MHz, chloroform-d) δ=7.73-7.62 (m, 2H), 7.46-7.38 (m, 1H),7.38-7.32 (m, 1H), 7.27-7.17 (m, 2H), 5.55-5.32 (m, 1H), 5.26 (dd,J=3.6, 16.8 Hz, 1H), 5.08-4.63 (m, 1H), 4.53-4.39 (m, 1H), 4.37-4.26 (m,1H), 4.25-4.00 (m, 3H), 3.97-3.71 (m, 3H), 3.59-3.35 (m, 2H), 3.29-2.98(m, 4H), 2.91 (d, J=5.6 Hz, 8H), 2.69-2.58 (m, 1H), 2.57-2.45 (m, 1H),2.42-2.29 (m, 1H), 2.28-2.14 (m, 1H), 2.06-1.91 (m, 1H).

Example 570

2-[(2S)-1-(2-Fluoroprop-2-enoyl)-4-[2-[[(2R,3R)-3-hydroxy-1-methyl-5-oxo-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

(2R)-2-(tert-Butoxycarbonylamino)-3-[tert-butyl(diphenyl)silyl]oxy-propanoicacid. To a of solution of(2R)-2-(tert-butoxycarbonylamino)-3-hydroxy-propanoic acid (27 g, 132mmol, 1 eq) in DMF (270 mL) was added imidazole (45.4 g, 667 mmol, 5.07eq) at 0° C. under nitrogen. After the solution became clear, TBDPSCl(90.4 g, 329 mmol, 84.5 mL, 2.5 eq) was added. The reaction was warmedto 15° C. After stirring at 15° C. for 24 h, the reaction mixture wasconcentrated under vacuum, diluted with ether (250 ml) and poured intosaturated NaCl (100 mL). The separated of organic layer was washed witha mixture of 10% HCl (25 mL) and saturated NaCl (50 mL), dried overNa₂SO₄ and concentrated under reduced pressure. The residue was dilutedwith acetonitrile and then white precipitate was formed. The precipitatewas filtered and the filter cake was dried under vacuum to give(2R)-2-(tert-butoxycarbonylamino)-3-[tert-butyl(diphenyl)silyl]oxy-propanoicacid (45 g, 90 mmol, 69% yield, 89% purity) as a white solid.

tert-Butyl N-[(1R)-1-[[tert-butyl(diphenyl)silyl]oxymethyl]-2-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-2-oxo-ethyl]carbamate.To a stirred solution of (2R)-2-tert-butoxycarbonylamino)-3-[tert-butyl(diphenyl)silyl]oxy-propanoic acid (24 g, 54.1 mmol, 1 eq) in DCM (400mL) at 0° C. was added 2,2-dimethyl-1,3-dioxane-4,6-dione (8.19 g, 56.8mmol, 1.05 eq) and DMAP (16.0 g, 131 mmol, 2.42 eq), followed by BOP(25.1 g, 56.8 mmol, 1.05 eq) in small portions. The mixture was stirredfor 1 hour at 0° C. Upon completion, the mixture was washed with 1NKHSO₄ (2×360 mL). The organic layers were dried over Na₂SO₄ andconcentrated under vacuum at room temperature to give tert-butylN-[(1R)-1-[[tert-butyl(diphenyl)silyl]oxymethyl]-2-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-2-oxo-ethyl]carbamate(35 g, crude) as a yellow oil which as used directly into the next stepwithout further purification.

tert-Butyl(2R)-2-[[tert-butyl(diphenyl)silyl]oxymethyl]-3,5-dioxo-pyrrolidine-1-carboxylate.tert-butylN-[(1R)-1-[[tert-butyl(diphenyl)silyl]oxymethyl]-2-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-2-oxo-ethyl]carbamate(35 g, 61.43 mmol, 1 eq) was refluxed in EtOAc (600 mL) at 77° C. for 1hour. Upon completion, the mixture was concentrated under vacuum to givetert-butyl(2R)-2-[[tert-butyl(diphenyl)silyl]oxymethyl]-3,5-dioxo-pyrrolidine-1-carboxylate(30 g, crude) as a yellow oil which used directly in the next stepwithout further purification.

tert-Butyl(2R/3R)-2-[[tert-butyl(diphenyl)silyl]oxymethyl]-3-hydroxy-5-oxo-pyrrolidine-1-carboxylate.tert-butyl(2R)-2-[[tert-butyl(diphenyl)silyl]oxymethyl]-3,5-dioxo-pyrrolidine-1-carboxylate(30 g, 64.2 mmol, 1 eq) was dissolved in DCM (480 mL) at 0° C., followedby NaBH₄ (3.78 g, 99.9 mmol, 1.56 eq) in small portions. The suspensionwas stirred at 18° C. for 16 hours. Upon completion, the reactionmixture was poured into water (300 ml) and stirred until no solidremained. The separated organic layer was washed with water (150 mL),dried over Na₂SO₄ filtered and concentrated under vacuum. The residuewas purified by silica gel chromatography (PE/EtOAc 10/1 to 2/1)followed by reverse phase flash [water (0.1% FA)/acetonitrile]. Thedesired fractions were collected and neutralized with NaHCO₃,concentrated under vacuum to remove MeCN, and then extracted with DCM(2×50 mL). The organic layers were dried over Na₂SO₄ and concentratedunder vacuum to give tert-butyl(2R,3R)-2-[[tert-butyl(diphenyl)silyl]oxymethyl]-3-hydroxy-5-oxo-pyrrolidine-1-carboxylate(2.13 g, 3.99 mmol, three steps 7.6% yield, 88% purity) as a yellowsolid.

¹H NMR (400 MHz, DMSO-d₆) δ=7.72 (dd, J=1.6, 8.0 Hz, 2H), 7.59 (dd,J=1.2, 8.0 Hz, 2H), 7.47-7.39 (m, 6H), 5.67 (d, J=4.0 Hz, 1H), 4.57-4.46(m, 1H), 4.09-3.97 (m, 2H), 3.83 (dd, J=2.8, 10.0 Hz, 1H), 2.75-2.65 (m,1H), 2.62-2.53 (m, 1H), 1.38 (s, 9H), 0.93 (s, 9H).

tert-Butyl (2R,3R)-2-[[tert-butyl(diphenyl)silyl]oxymethyl]-5-oxo-3-tetrahydropyran-2-yloxy-pyrrolidine-1-carboxylate.To a solution of tert-butyl (2R,3R)-2-[[tert-butyl(diphenyl)silyl]oxymethyl]-3-hydroxy-5-oxo-pyrrolidine-1-carboxylate (2.55 g, 5.43 mmol,1 eq) in DCM (50 mL) was added DHP (913 mg, 10.9 mmol, 993 μL, 2 eq),followed by TsOH·H₂O (103 mg, 543 μmol, 0.1 eq) at 20° C. The mixturewas stirred at 20° C. for 16 hours. Upon completion, the mixture wasquenched with saturated aqueous NaHCO₃ solution (10 mL), diluted withwater (5 mL) and extracted with DCM (2×40 mL). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated under vacuum.The residue was purified by silica gel chromatography (PE/EtOAc 15/1 to7/1) to give tert-butyl (2R,3R)-2-[[tert-butyl(diphenyl)silyl]oxymethyl]-5-oxo-3-tetrahydropyran-2-yloxy-pyrrolidine-1-carboxylate(2.62 g, 4.64 mmol, 85% yield, 98% purity) as a yellow solid.

¹H NMR (400 MHz, chloroform-d) δ=7.75 (td, J=1.2, 7.6 Hz, 2H), 7.66 (td,J=1.6, 8.0 Hz, 2H), 7.47-7.34 (m, 6H), 4.75-4.68 (m, 1H), 4.63-4.51 (m,1H), 4.20-4.17 (m, 1H), 3.99-3.88 (m, 2H), 3.87-3.74 (m, 1H), 3.60-3.50(m, 1H), 3.23-3.01 (m, 1H), 2.76 (ddd, J=8.8, 10.4, 16.8 Hz, 1H),2.01-1.80 (m, 2H), 1.79-1.62 (m, 4H), 1.45 (s, 9H), 1.02 (d, J=8.0 Hz,9H).

(4R,5R)-5-[[tert-Butyl(diphenyl)silyl]oxymethyl]-4-tetrahydropyran-2-yloxy-pyrrolidin-2-one. To asolution of tert-butyl (2R,3R)-2-[[tert-butyl(diphenyl)silyl]oxymethyl]-5-oxo-3-tetrahydropyran-2-yloxy-pyrrolidine-1-carboxylate(2.62 g, 4.73 mmol, 1 eq) in MeCN (50 mL) was added Mg(ClO₄)₂ (211 mg,946 μmol, 95.6 μL, 0.2 eq). The reaction mixture was stirred at 70° C.for 12 hours. Upon completion, the mixture was filtered and the filtratewas concentrated under vacuum. The residue was purified by reverse phaseflash [water (0.1% FA)/acetonitrile]. The desired fractions werecollected and concentrated under vacuum to give(4R,5R)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]-4-tetrahydropyran-2-yloxy-pyrrolidin-2-one (1.14 g,2.29 mmol, 48% yield, 91% purity) as a yellow oil. LC MS [ESI, M+1]:454.

(4R,5R)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]-1-methyl-4-tetrahydropyran-2-yloxy-pyrrolidin-2-one.To a solution of(4R,5R)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]4-tetrahydropyran-2-yloxy-pyrrolidin-2-one(0.95 g, 2.09 mmol, 1 eq) in THF (20 mL) was added NaH (168 mg, 4.19mmol, 60% purity in mineral oil, 2 eq) in portion at 0° C. under N₂. Themixture was stirred at 0° C. for 30 minutes, then CH₃I (594 mg, 4.19mmol, 261 uL, 2 eq) was added. After stirred at 0° C. for another 0.5hour, the mixture was quenched with water (10 mL) and extracted withEtOAc (2×30 mL). The organic layers were dried over Na₂SO₄ andconcentrated under vacuum. The residue was purified by reverse phaseflash [water (0.1% FA)/acetonitrile]. The desired fractions werecollected and concentrated under vacuum to give(4R,5R)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]-1-methyl-4-tetrahydropyran-2-yloxy-pyrrolidin-2-one(820 mg, 1.67 mmol, 80% yield, 95% purity) as a brown oil.

¹H NMR (400 MHz, chloroform-d) δ=7.75-7.70 (m, 2H), 7.70-7.65 (m, 2H),7.48-7.36 (m, 6H), 4.68-4.60 (m, 1H), 4.59-4.48 (m, 1H), 4.07-3.77 (m,2H), 3.77-3.66 (m, 1H), 3.65-3.56 (m, 1H), 3.55-3.40 (m, 1H), 2.89-2.79(m, 3H), 2.79-2.53 (m, 2H), 1.90-1.69 (m, 2H), 1.68-1.53 (m, 4H),1.09-1.03 (m, 9H).

(4R,5R)-5-(Hydroxymethyl)-1-methyl-4-tetrahydropyran-2-yloxy-pyrrolidin-2-one.To a mixture of (4R,5R)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]-1-methyl-4-tetrahydropyran-2-yloxy-pyrrolidin-2-one (1.07 g,2.29 mmol, 1 eq) in DMSO (10 mL) was added CsF (1.04 g, 6.86 mmol, 253μL, 3 eq). The mixture was stirred at 65° C. for 2 hours. Uponcompletion, the mixture was concentrated under vacuum. The residue waspurified by chromatography (Al₂O₃, EtOAc/MeOH 50/1 to 5/1) to give(4R,5R)-5-(hydroxymethyl)-1-methyl-4-tetrahydropyran-2-yloxy-pyrrolidin-2-one(380 mg, 1.49 mmol, 65% yield, 90% purity) as a yellow oil.

¹H NMR (400 MHz, chloroform-d) δ=4.80-4.52 (m, 2H), 3.98-3.81 (m, 3H),3.72-3.61 (m, 1H), 3.60-3.48 (m, 1H), 2.87 (d, J=9.6 Hz, 3H), 2.67 (d,J=7.2 Hz, 1H), 2.60-2.46 (m, 1H), 1.86-1.74 (m, 2H), 1.67-1.51 (m, 4H).

Step A: Benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R,3R)-1-methyl-5-oxo-3-tetrahydropyran-2-yloxy-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(280 mg, 471 μmol, 1 eq) and(4R,5R)-5-(hydroxymethyl)-1-methyl-4-tetrahydropyran-2-yloxy-pyrrolidin-2-one(140 mg, 612 μmol, 1.3 eq) in toluene (6 mL) was added t-BuONa (90.5 mg,942 μmol, 2 eq) at 0° C. After stirred at 0° C. for 10 minutes, themixture was diluted with water (5 mL) and extracted with EtOAc (2×10mL). The organic layers were dried over Na₂SO₄ and concentrated undervacuum. The residue was purified by reverse phase flash [water (0.1%FA)/acetonitrile]. The desired fractions were collected and neutralizedwith NaHCO₃, concentrated under vacuum to remove MeCN and extracted withEtOAc (2×20 mL). The organic layers were dried over Na₂SO₄ andconcentrated under vacuum to give benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R,3R)-1-methyl-5-oxo-3-tetrahydropyran-2-yloxy-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 258 μmol, 55% yield, 98% purity) as a yellow solid. LCMS [ESI,M+1]: 760.

¹H NMR (400 MHz, chloroform-d) δ=7.74-7.63 (m, 2H), 7.47-7.31 (m, 7H),7.27-7.17 (m, 2H), 5.21 (s, 2H), 4.84-4.43 (m, 5H), 4.30-3.70 (m, 8H),3.59-3.34 (m, 3H), 3.25-2.98 (m, 4H), 2.96-2.90 (m, 6H), 2.81-2.56 (m,41H), 1.83-1.63 (m, 2H), 1.60-1.47 (m, 41H).

Step B:2-[(2S)-4-[7-(8-Methyl-1-naphthyl)-2-[[(2R,3R)-1-methyl-5-oxo-3-tetrahydropyran-2-yloxy-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R,3R)-1-methyl-5-oxo-3-tetrahydropyran-2-yloxy-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(150 mg, 197 μmol, 1 eq) in MeOH (3 mL) was added NH₃/MeOH (3 mL, 20%purity), Pd/C (75 mg, 10% purity) under N₂. The suspension was degassedunder vacuum and purged with H₂ several times. The mixture was stirredunder H₂ (15 psi) at 20° C. for 1 hour. Upon completion, the mixture wasfiltered and the filtrate was concentrated under vacuum to give2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R,3R)-1-methyl-5-oxo-3-tetrahydropyran-2-yloxy-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(100 mg, 144 μmol, 73% yield, 90% purity) as a yellow solid which wasused directly in the next step without further purification. LCMS [ESI,M+1]: 626.

Step C:2-[(2S)-4-[2-[[(2R,3R)-3-Hydroxy-1-methyl-5-oxo-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R,3R)-1-methyl-5-oxo-3-tetrahydropyran-2-yloxy-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(100 mg, 160 μmol, 1 eq) in DCM (100 μL) was added TFA (273 mg, 2.40mmol, 177 μL, 15 eq). The mixture was stirred at 20° C. for 1 hour. Uponcompletion, the mixture was diluted with DCM (5 mL) and basified withsaturated sodium bicarbonate aqueous solution to pH=8. The separatedaqueous layer was extracted with EtOAc (3×5 mL). Combined organic layerswere dried over MgSO₄, filtered and concentrated under vacuum to give2-[(2S)-4-[2-[[(2R,3R)-3-hydroxy-1-methyl-5-oxo-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(80 mg, 126 μmol, 79% yield, 85% purity) as a yellow oil which was useddirectly in the next step without further purification.

Step D:2-[(2S)-1-(2-Fluoroprop-2-enoyl)-4-[2-[[(2R,3R)-3-hydroxy-1-methyl-5-oxo-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[2-[[(2R,3R)-3-hydroxy-1-methyl-5-oxo-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(80 mg, 148 μmol, 1 eq), TEA (44.8 mg, 443 μmol, 61.7 μL, 3 eq) and2-fluoroprop-2-enoic acid (26.6 mg, 295 μmol, 2 eq) in EA (3 mL) wasadded T3P (141 mg, 222 μmol, 132 uL, 50% purity in EtOAc, 1.5 eq) at 0°C. The mixture was stirred at 0° C. for 0.5 hour. Upon completion, themixture was quenched with saturated NaHCO₃ aqueous solution (5 mL) andextracted with EtOAc (2×10 mL). The organic layers were dried overNa₂SO₄ and concentrated under vacuum. The residue was purified bychromatography (Al₂O₃, EtOAc/MeOH 1/0 to 10/1) followed by prep-HPLC(column: Xtimate C18 150*25 mm*5 um; mobile phase: [water (0.05%ammonium hydroxide v/v)-ACN]; B %: 34%-64%, 10 min). The desiredfractions were collected and lyophilized to give title compound2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[2-[[(2R,3R)-3-hydroxy-1-methyl-5-oxo-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(11.8 mg, 19.1 μmol, 13% yield, 99.3% purity) as a off-white solid. LCMS[ESI, M+1]: 614.

¹H NMR (400 MHz, chloroform-d) δ=7.71 (d, J=8.0 Hz, 1H), 7.69-7.63 (m,1H), 7.41 (q, J=7.6 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 7.27-7.19 (m, 2H),5.55-5.33 (m, 1H), 5.27 (dd, J=3.6, 16.8 Hz, 1H), 4.86 (dd, J=5.6, 12.0Hz, 1H), 4.79 (dd, J=5.6, 12.0 Hz, 1H), 4.63-4.49 (m, 2H), 4.39-3.94 (m,3H), 3.89-3.77 (m, 2H), 3.76-3.63 (m, 1H), 3.61-3.44 (m, 2H), 3.38-2.99(m, 4H), 2.91 (d, J=7.2 Hz, 6H), 2.89-2.70 (m, 2H), 2.70-2.55 (m, 2H),2.46 (dt, J=5.2, 16.0 Hz, 1H).

Example 571

2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-((S)-pyrrolidin-2-ylmethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

Step A: tert-Butyl(2S)-2-[(7-benzyl-4-methoxy-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl)oxymethyl]pyrrolidine-1-carboxylate.To a solution of7-benzyl-2-chloro-4-methoxy-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (4.00g, 13.8 mmol, 1.00 eq) and tert-butyl(2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (5.56 g, 27.6 mmol, 2.00eq) in toluene (80.0 mL) was added BINAP (1.72 g, 2.76 mmol, 0.20 eq),Pd(OAc)₂ (310 mg, 1.38 mmol, 0.10 eq) and Cs₂CO₃ (13.5 g, 41 mmol, 3.00eq). The mixture was stirred at 110° C. for 8 hours. After completion,the reaction mixture was filtered and concentrated under reducedpressure to give a residue. The residue was diluted with H₂O (200 mL)and ethyl acetate (200 mL). The mixture was acidified to pH˜3 withaqueous HCl (2N). The aqueous phase was separated and extracted withethyl acetate (3×200 mL). The combined organic layers were dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (SiO₂,petroleum ether/ethyl acetate=20/1 to 1/1) to give tert-butyl(2S)-2-[(7-benzyl-4-methoxy-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl)oxymethyl]pyrrolidine-1-carboxylate (3.80 g, 8.26 mmol, 60% yield, 99%purity) as yellow oil. LCMS [ESI, M+1]: 455.

¹H NMR (400 MHz, chloroform-d) δ 7.37-7.27 (m, 5H), 4.50-4.35 (m, 1H),4.25-4.16 (m, 1H), 3.98 (s, 3H), 3.69 (s, 2H), 3.50 (s, 2H), 3.43-3.33(m, 2H), 2.76-2.72 (m, 2H), 2.62-2.57 (m, 2H), 2.04-1.90 (m, 3H),1.85-1.76 (m, 1H), 1.61-1.54 (m, 1H), 1.45 (s, 9H).

Step B: tert-Butyl (2S)-2-[(4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxymethyl]pyrrolidine-1-carboxylate. To a solution oftert-butyl(2S)-2-[(7-benzyl-4-methoxy-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl)oxymethyl]pyrrolidine-1-carboxylate(3.80 g, 8.36 mmol, 1.00 eq) in methanol (100 mL) was added Pd(OH)₂/C(1.00 g, 10.3 mmol, 20% purity) under N₂. The suspension was degassedunder vacuum and purged with H₂ three times. The mixture was stirredunder H₂ (45 psi) at 40° C. for 24 hours. After completion, the reactionmixture was concentrated under reduced pressure to give a residue.Compound tert-butyl (2S)-2-[(4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxymethyl]pyrrolidine-1-carboxylate (2.70 g, 7.17 mmol,86% yield, 97% purity) was obtained as yellow oil and used into the nextstep without further purification. LCMS [ESI, M+1]: 365.

¹H NMR (400 MHz, chloroform-d) δ 4.54-4.35 (m, 1H), 4.25-4.10 (m, 2H),3.98 (s, 3H), 3.86 (s, 2H), 3.48 (s, 1H), 3.43-3.33 (m, 2H), 3.13-3.04(m, 2H), 2.56-2.46 (m, 2H), 2.10-1.93 (m, 3H), 1.87-1.82 (m, 1H), 1.45(s, 9H).

Step C: tert-Butyl(2S)-2-[[7-(8-chloro-1-naphthyl)-4-methoxy-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate.To a solution of tert-butyl(2S)-2-[(4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxymethyl]pyrrolidine-1-carboxylate(2.5 g, 6.86 mmol, 1.0 eq) and 1-bromo-8-chloro-naphthalene (3.31 g,13.7 mmol, 2.0 eq) in toluene (50 mL) was added Pd₂(dba)₃ (1.26 g, 1.37mmol, 0.2 eq), Cs₂CO₃ (5.59 g, 17.2 mmol, 2.5 eq), and RuPhos (1.28 g,2.74 mmol, 0.4 eq), the reaction mixture was stirred at 90° C. for 12hours under N₂. After completion, the reaction mixture was filteredthrough celite, and the filtrate was washed with saturated brine (1×80mL), the organic layer was dried over Na₂SO₄, filtered and concentrated.The residue was purified by column chromatography (SiO₂, petroleumether/ethyl acetate=10/1 to 3/1). The product tert-butyl(2S)-2-[[7-(8-chloro-1-naphthyl)-4-methoxy-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate(1.3 g, 2.46 mmol, 36% yield, 99% purity) as light yellow solid. LCMS[ESI, M+1]: 525.

¹H NMR (400 MHz, chloroform-d) δ 7.74 (d, J=8.4 Hz, 1H), 7.60 (br d,J=8.0 Hz, 1H), 7.51 (d, J=7.6 Hz, 1H), 7.43 (t, J=7.8 Hz, 1H), 7.33 (t,J=7.8 Hz, 1H), 7.23 (br d, J=7.6 Hz, 1H), 4.60-4.37 (m, 1H), 4.34-4.16(m, 3H), 4.03 (s, 3H), 3.87 (br d, J=17.2 Hz, 1H), 3.63-3.57 (m, 1H),3.45-3.30 (m, 2H), 3.21-3.10 (m, 1H), 2.99 (br s, 1H), 2.62 (br d,J=16.8 Hz, 1H), 2.07-1.79 (m, 4H), 1.45 (s, 9H).

Step D: tert-Butyl(2S)-2-[[7-(8-chloro-1-naphthyl)-4-hydroxy-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate.To a solution of NaH (168 mg, 4.19 mmol, 60% purity, 2.0 eq) in DMF (15mL) was added EtSH (391 mg, 6.29 mmol, 465 μL, 3.0 eq) in portions at15° C. After stirring for 0.5 hour, a solution oftert-butyl(2S)-2-[[7-(8-chloro-1-naphthyl)-4-methoxy-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate(1.1 g, 2.10 mmol, 1.0 eq) in DMF (7.0 mL) was added to the mixture,then the reaction mixture was stirred at 60° C. for 1 hour. Aftercompletion, the reaction mixture was poured into ice water (10 mL), thenthe mixture was adjusted with 1N HCl aqueous to pH 7˜8, the mixture wasfiltered, the filter cake was dissolved with dichloromethane (10 mL),washed with saturated brine (2×15 mL), dried over NaSO₄, filtered andconcentrated. The residue was purified by column chromatography (SiO₂,petroleum ether/ethyl acetate=3/1 to ethyl acetate:methanol=10:1) togive tert-butyl(2S)-2-[[7-(8-chloro-1-naphthyl)-4-hydroxy-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate(670 mg, 1.28 mmol, 61% yield, 98% purity) as yellow solid. LCMS [ESI,M+1]: 511.

Step E:tert-Butyl(2S)-2-[[7-(8-chloro-1-naphthyl)-4-(trifluoromethylsulfonyloxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate.To a solution of tert-butyl(2S)-2-[[7-(8-chloro-1-naphthyl)-4-hydroxy-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate(640 mg, 1.25 mmol, 1.0 eq) in DCM (10 mL) was added TEA (380 mg, 3.76mmol, 523 μL, 3.0 eq), 4A molecular sieves (500 mg), and Tf₂O (530 mg,1.88 mmol, 310 μL, 1.5 eq) at −40° C., and the reaction mixture wasstirred at −40° C. for 10 mins. After completion, water was added (10mL) in portions at −40° C., then the reaction mixture was warmed to 15°C. and the organic layer was separated and washed with saturated brine(1×10 mL), the organic layer was dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography (SiO₂,petroleum ether/ethyl acetate=10/1 to 3/1). The producttert-butyl(2S)-2-[[7-(8-chloro-1-naphthyl)-4-(trifluoromethylsulfonyloxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate(400 mg, 616 μmol, 49% yield, 99% purity) was obtained as light yellowsolid. LCMS [ESI, M+1]: 643.

Step F: tert-Butyl(2S)-2-[[7-(8-chloro-1-naphthyl)-4[(3S)-3-(cyanomethyl)piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate.To a solution of tert-butyl(2S)-2-[[7-(8-chloro-1-naphthyl)-4-(trifluoromethylsulfonyloxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate(400 mg, 622 μmol, 1.0 eq) in DMAC (4.0 mL) was added2-[(2S)-piperazin-2-yl]acetonitrile (86.5 mg, 622 μmol, 1.0 eq) and DIEA(161 mg, 1.24 mmol, 217 μL, 2.0 eq), the reaction mixture was stirred at15° C. for 10 mins. After completion, the reaction mixture was pouredinto ice water (10 mL), the precipitated solid was filtered, dissolvedwith ethyl acetate (15 mL), the organic layer was washed with saturatedbrine (2×15 mL), dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by reverse phase flash (0.1% FA condition, 20%-30%MeCN in water), the obtained product was adjusted with NaHCO₃ solid topH˜8, then concentrated, the aqueous was extracted with ethyl acetate(2×15 mL), the organic layer was washed with saturated brine (1×20 mL),dried over Na₂SO₄, filtered and concentrated. The product tert-butyl(2S)-2-[[7-(8-chloro-1-naphthyl)-4[(3S)-3-(cyanomethyl)piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate(300 mg, 480 μmol, 77% yield, 990 purity) was obtained as light yellowsolid. LCMS [ESI, M+1]: 618.

¹H NMR (400 MHz, chloroform-d) δ 7.75 (d, J=8.0 Hz, 1H), 7.61 (br d,J=8.0 Hz, 1H), 7.52 (d, J=6.8 Hz, 1H), 7.47-7.42 (m, 1H), 7.33 (t, J=7.8Hz, 1H), 7.23 (br t, J=6.2 Hz, 1H), 4.71-4.31 (m, 2H), 4.29-4.06 (m,3H), 3.95-3.69 (m, 2H), 3.63-3.28 (m, 4H), 3.26-2.82 (m, 7H), 2.72-2.46(m, 3H), 2.02-1.79 (m, 4H), 1.45 (s, 9H).

Step G:tert-Butyl(2S)-2-[[7-(8-chloro-1-naphthyl)-4-[(3S)-3-(cyanomethyl)-4-(2-fluoroprop-2-enoyl)piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate.To a solution of tert-butyl(2S)-2-[[7-(8-chloro-1-naphthyl)-4-[(3S)-3-(cyanomethyl)piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate(100 mg, 162 μmol, 1.0 eq) and 2-fluoroprop-2-enoic acid (29.1 mg, 324μmol, 2.0 eq) in ethyl acetate (1.5 mL) was added TEA (131 mg, 1.29mmol, 180 μL, 8.0 eq) and T3P (309 mg, 485 μmol, 289 μL, 50% purity, 3.0eq) in portions at 0° C., the reaction mixture was stirred at 0° C. for1 hour. After completion, water was added (10 ml), then the organiclayer was separated, the aqueous phase was extracted with ethyl acetate(2×10 mL), the combined organic layer was dried over Na₂SO₄, filteredand concentrated. The residue was purified column chromatography (basicAl₂O₃, petroleum ether/ethyl acetate=3/1 to 1/1). The producttert-butyl(2S)-2-[[7-(8-chloro-1-naphthyl)-4-[(3S)-3-(cyanomethyl)-4-(2-fluoroprop-2-enoyl)piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate(110 mg, crude) was obtained as light yellow solid LCMS [ESI, M+1]: 690.

Step H:2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-((S)-pyrrolidin-2-ylmethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile.To a solution of tert-butyl(2S)-2-[[7-(8-chloro-1-naphthyl)-4-[(3S)-3-(cyanomethyl)-4-(2-fluoroprop-2-enoyl)piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate(90.0 mg, 130.40 μmol, 1.0 eq) in dichloromethane (0.5 mL) was added TFA(770 mg, 6.75 mmol, 0.5 mL, 51.8 eq), and the reaction mixture wasstirred at 20° C. for 1 hour. After completion, the reaction mixture wasconcentrated, then dissolved with ethyl acetate (10 mL), washed withsaturated aqueous Na₂CO₃ (1×10 mL), the organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was purified by columnchromatography (SiO₂, petroleum ether/ethyl acetate=3/1 to ethylacetate:methanol=10:1), then purified by prep-HPLC (column: PhenomenexSynergi C18 150*25*10 μm; mobile phase: [water (0.225% FA)-ACN]; B %:20%-50%, 10 min), the obtained product was concentrated and lyophilized.Title compound2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-((S)-pyrrolidin-2-ylmethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile(24.7 mg, 38.1 μmol, 29% yield, 98% purity, FA) was obtained asoff-white solid. LCMS [ESI, M+1]: 590.

¹H NMR (400 MHz, chloroform-d) δ 7.76 (d, J=8.0 Hz, 1H), 7.62 (t, J=7.0Hz, 1H), 7.56-7.49 (m, 1H), 7.54-7.50 (m, 1H), 7.34 (t, J=7.8 Hz, 1H),7.26-7.17 (m, 1H), 5.53-5.32 (m, 1H), 5.25 (dd, J=3.6, 16.8 Hz, 1H),4.89-4.52 (m, 1H), 4.64-4.45 (m, 2H), 4.42-4.23 (m, 2H), 4.17-3.92 (m,41H), 3.89-3.78 (m, 2H), 3.51-3.42 (m, 1H), 3.35-3.05 (m, 5H), 2.95-2.73(m, 2H), 2.62-2.51 (m, 1H), 2.21-1.84 (m, 4H).

Example 572

2-[(2S)-4-[7-(8-Chloro-1-naphthyl)-2-[[(2S)-1-methyl-5-oxo-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile

Step A: tert-Butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methyl-5-oxo-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.To a mixture of (5S)-5-(hydroxymethyl)-1-methyl-pyrrolidin-2-one (556mg, 4.30 mmol, 5.00 eq) in THF (20.0 mL) was added t-BuONa (827 mg, 8.60mmol, 10.0 eq) in portion at 0° C. under N₂. The mixture was stirred at0° C. for 30 min, followed by adding tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(500 mg, 860 μmol, 1.00 eq). The mixture was warmed to 15° C. andstirred for 0.5 hour. The reaction mixture was diluted with ethylacetate (50.0 mL) and washed with water (30 mL×2), dried over sodiumsulfate, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by reverse phase flash [water (0.1%TFA)/acetonitrile]. The desired fractions were collected and neutralizedwith saturated NaHCO₃ solution (10.0 mL) and extracted with ethylacetate (50.0 mL×3). The separated organic layer was dried over sodiumsulfate, filtered and concentrated under vacuum. Compound tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methyl-5-oxo-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(125 mg, 193 μmol, 22% yield) was obtained as a yellow solid.

¹H NMR (400 MHz, chloroform-d) δ=7.75 (d, J=8.0 Hz, 1H), 7.61 (dd,J=4.8, 8.0 Hz, 1H), 7.52 (dd, J=0.8, 7.2 Hz, 1H), 7.45 (q, J=8.0 Hz,1H), 7.37-7.28 (m, 1H), 7.23 (br d, J=7.6 Hz, 1H), 4.70-4.31 (m, 3H),4.10-3.82 (m, 4H), 3.65-3.51 (m, 1H), 3.46-2.99 (m, 5H), 2.98-2.82 (m,3H), 2.79-2.37 (m, 5H), 2.22 (br d, J=8.0 Hz, 1H), 1.93-1.59 (m, 3H),1.52 (s, 9H).

Step B:2-[(2S)-4-[7-(8-Chloro-1-naphthyl)-2-[[(2S)-1-methyl-5-oxo-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a mixture of tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methyl-5-oxo-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(100 mg, 155 μmol, 1.00 eq) in dioxane (1.50 mL) was added HCl/dioxane(4 M, 967 μL, 25.0 eq). The mixture was stirred at 20° C. for 1 h. Thereaction mixture was concentrated under reduced pressure to give aresidue. The residue was dissolved with ethyl acetate (10.0 mL) andbasified to pH=8 with saturated NaHCO₃ solution (3.00 mL), and extractedwith ethyl acetate (5.00 mL×3). The combined organic layers were washedwith brine (10.0 mL×1), dried over sodium sulfate, filtered andconcentrated under reduced pressure to give a residue. The crude productwas used in the next step directly without further purification.Compound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methyl-5-oxo-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(80.0 mg, crude) was obtained as a yellow solid. LCMS [ESI, M+1]: 546.

Step C:2-[(2S)-4-[7-(8-Chloro-1-naphthyl)-2-[[(2S)-1-methyl-5-oxo-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.To a mixture of2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methyl-5-oxo-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(60.0 mg, 110 μmol, 1.00 eq) and 2-fluoroprop-2-enoic acid (19.8 mg, 220μmol, 2.00 eq) in EA (1 mL) was added TEA (89.0 mg, 879 μmol, 122 μL,8.00 eq), T3P (210 mg, 330 mol, 196 μL, 50% purity in ethyl acetate,3.00 eq) in portion at 0° C. under N₂. The mixture was stirred at 0° C.for 30 min. The reaction mixture was diluted with water (5 mL) andextracted with ethyl acetate (10 mL×3). The combined organic layers werewashed with water (10 mL×1) and brine (10 mL×1), dried over sodiumsulfate, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by prep-HPLC (column: Xtimate C18150×25 mm×5 μm; mobile phase: [water (0.05% ammonium hydroxidev/v)-ACN]; B;%: 35%-65%, 10 min). Title compound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methyl-5-oxo-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile(11.3 mg, 18.2 umol, 17% yield, 99% purity) was obtained as a whitesolid LCMS [ESI, M+1]: 618.

¹H NMR (400 MHz, chloroform-d) δ=7.77 (d, J=8.0 Hz, 1H), 7.63 (t, J=7.6Hz, 1H), 7.53 (d, J=6.8 Hz, 1H), 7.46 (td, J=8.0, 10.4 Hz, 1H), 7.35 (t,J=7.6 Hz, 1H), 7.27-7.20 (m, 1H), 5.52-5.34 (m, 1H), 5.26 (dd, J=3.6,16.8 Hz, 1H), 4.92 (br s, 1H), 4.52-4.31 (m, 3H), 4.27-3.77 (m, 5H),3.61 (br d, J=10.8 Hz, 1H), 3.46 (br d, J=12.0 Hz, 1H), 3.36-2.94 (m,5H), 2.92 (s, 3H), 2.90-2.79 (m, 1H), 2.64-2.48 (m, 2H), 2.41-2.31 (m,1H), 2.28-2.17 (m, 1H), 2.05-1.95 (m, 1H).

Example 573

2-[(2S)-4-[7-(8-Chloro-1-naphthyl)-2-[[(2R,3R)-3-hydroxy-1-methyl-5-oxo-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile

Step A: tert-Butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R,3R)-1-methyl-5-oxo-3-tetrahydropyran-2-yloxy-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.To a solution of tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(280 mg, 482 μmol, 1 eq) and(4R,5R)-5-(hydroxymethyl)-1-methyl-4-tetrahydropyran-2-yloxy-pyrrolidin-2-one(144 mg, 626 μmol, 1.3 eq) in toluene (6 mL) was added t-BuONa (92.6 mg,964 μmol, 2 eq). The mixture was stirred at 0° C. for 10 minutes. Uponcompletion, the mixture was diluted with water (5 mL) and extracted withEtOAc (2×10 mL). The organic layers were dried over Na₂SO₄ andconcentrated under vacuum. The residue was purified by reverse phaseflash [water (0.1% FA)/acetonitrile]. The desired fractions werecollected and neutralized with NaHCO₃, concentrated under vacuum toremove MeCN and extracted with EtOAc (2×20 mL). The organic layers weredried over Na₂SO₄ and concentrated under vacuum to give tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R,3R)-1-methyl-5-oxo-3-tetrahydropyran-2-yloxy-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(280 mg, 345 μmol, 72′% yield, 92% purity) as a yellow solid. LCMS [ESI,M+1]: 746.

¹H NMR (400 MHz, chloroform-d) δ=7.76 (br d, J=8.0 Hz, 1H), 7.66-7.57(m, 1H), 7.53 (d, J=7.2 Hz, 1H), 7.50-7.41 (m, 1H), 7.37-7.31 (m, 1H),7.27-7.18 (m, 1H), 4.88-4.69 (m, 1H), 4.68-4.47 (m, 4H), 4.46-4.35 (m,1H), 4.11-3.74 (m, 6H), 3.65-3.48 (m, 2H), 3.44-2.99 (m, 5H), 2.96 (dd,J=2.8, 8.4 Hz, 3H), 2.91-2.51 (m, 5H), 1.81-1.64 (m, 2H), 1.52 (s, 13H).

Step B:2-[(2S)-4-[7-(8-Chloro-1-naphthyl)-2-[[(2R,3R)-3-hydroxy-1-methyl-5-oxo-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R,3R)-1-methyl-5-oxo-3-tetrahydropyran-2-yloxy-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(200 mg, 268 μmol, 1 eq) in DCM (0.15 mL) was added TFA (458 mg, 4.02mmol, 298 μL, 15 eq). The mixture was stirred at 20° C. for 1 hour. Uponcompletion, the mixture was diluted with DCM (5 mL) and basified withsaturated sodium bicarbonate aqueous solution to pH=8. The separatedaqueous layer was extracted with EtOAc (5×5 mL). Combined organic layerswere dried over MgSO₄, filtered and concentrated under vacuum to give2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R,3R)-3-hydroxy-1-methyl-5-oxo-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(150 mg, 230 μmol, 86% yield, 86% purity) as a yellow solid which wasused directly in the next step without further purification. LCMS [ESI,M+1]: 562.

Step C:2-[(2S)-4-[7-(8-Chloro-1-naphthyl-2-[((2R,3R)-3-hydroxy-1-methyl-5-oxo-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R,3R)-3-hydroxy-1-methyl-5-oxo-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(150 mg, 267 umol, 1 eq), TEA (81.0 mg, 801 umol, 111 uL, 3 eq) and2-fluoroprop-2-enoic acid (48.1 mg, 534 umol, 2 eq) in EtOAc (4 mL) wasadded T3P (255 mg, 400 umol, 238 uL, 50% purity in EtOAc, 1.5 eq) at 0°C. The mixture was stirred at 0° C. for 0.5 hour. Upon completion, themixture was quenched with saturated NaHCO₃ aqueous solution (5 mL) andextracted with EtOAc (2×10 mL). The organic layers were dried overNa₂SO₄ and concentrated under vacuum. The residue was purified bychromatography (Al₂O₃, EtOAc/MeOH 1/0 to 20/1) followed by prep-HPLC(column: Xtimate C18 150*25 mm*5 μm; mobile phase: [water (0.05%ammonium hydroxide v/v)-ACN]; B %: 33%-63%, 10 min). The desiredfractions were collected and lyophilized to give title compound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R,3R)-3-hydroxy-1-methyl-5-oxo-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile(22.0 mg, 34.5 umol, 13% yield, 99.6% purity) as a white solid. LCMS[ESI, M+1]: 634.

¹H NMR (400 MHz, chloroform-d) δ=7.77 (d, J=8.4 Hz, 1H), 7.64 (dd,J=4.4, 8.0 Hz, 1H), 7.54 (d, J=7.6 Hz, 1H), 7.46 (dt, J=6.0, 8.0 Hz,1H), 7.35 (t, J=7.6 Hz, 1H), 7.27-7.21 (m, 1H), 5.54-5.33 (m, 1H), 5.27(dd, J=2.8, 17.2 Hz, 1H), 4.88 (dd, J=1.6, 12.0 Hz, 1H), 4.80 (dd,J=6.0, 12.0 Hz, 1H), 4.64-4.48 (m, 2H), 4.47-3.94 (m, 4H), 3.91-3.65 (m,3H), 3.64-3.43 (m, 2H), 3.37-2.98 (m, 4H), 2.91 (d, J=7.6 Hz, 3H),2.89-2.76 (m, 1H), 2.70-2.53 (m, 2H), 2.46 (dt, J=5.2, 16.4 Hz, 1H).

Example 574

2-[(2S)-4-[7-(8-Chloro-1-naphthyl)-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile

Step A: tert-Butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.To a mixture of [(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methanol (275mg, 2.06 mmol, 2.0 eq) in toluene (12.0 mL) was added t-BuONa (198 mg,2.06 mmol, 2.0 eq) in portions at 0° C., after stirring at 0° C. for 0.5hour, tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(600 mg, 1.03 mmol, 1.0 eq) was added, and stirred at 0° C. for 0.5hour. After completion, water was added (15.0 mL), the resulting mixturewas extracted with ethyl acetate (2×10 mL), the combined organic layerwas dried over Na₂SO₄, filtered and concentrated. The residue waspurified by reverse phase flash (C18, 0.1% TFA in water, 30%-50% MeCN),the obtained product was adjusted with NaHCO₃ solid to pH=8, thenconcentrated, the aqueous phase was extracted with ethyl acetate (2×15mL), the organic layer was washed with saturated brine (20.0 mL), thendried over Na₂SO₄, filtered and concentrated. The product tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(510 mg, 769 μmol, 75% yield, 98% purity) was obtained as light yellowsolid. LCMS [ESI, M+1]: 650.

¹H NMR (400 MHz, chloroform-d) δ 7.80-7.72 (m, 1H), 7.62 (t, J=7.8 Hz,1H), 7.56-7.50 (m, 1H), 7.46-7.40 (m, 1H), 7.37-7.31 (m, 1H), 7.26-7.17(m, 1H), 5.29-5.07 (m, 1H), 4.65-4.57 (m, 1H), 4.50-4.34 (m, 2H),4.30-4.17 (m, 1H), 4.06-3.76 (m, 3H), 3.65-3.47 (m, 2H), 3.41-2.86 (m,7H), 2.84-2.45 (m, 7H), 2.40-2.24 (m, 1H), 2.04-1.86 (m, 1H), 1.52 (s,9H).

Step B:2-[(2S)-4-[7-(8-Chloro-1-naphthyl)-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(500 mg, 769 μmol, 1.0 eq) in dioxane (5.0 mL) was added 4N HCl·dioxane(5.0 mL), the reaction mixture was stirred at 15° C. for 1 hour. Aftercompletion, the reaction mixture was filtered, and the solid wasdissolved with dichloromethane (15.0 mL), the organic layer was washedwith saturated brine (1×15 mL), dried over Na₂SO₄, filtered andconcentrated to give2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(360 mg, 635 μmol, 85% yield, 97% purity) as light yellow solid LCMS[ESI, M+1]: 550.

Step C:2-[(2S)-4-[7-(8-Chloro-1-naphthyl)-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(120 mg, 218 μmol, 1.0 eq) and 2-fluoroprop-2-enoic acid (39.3 mg, 436μmol, 2.0 eq) in ethyl acetate (1.2 mL) was added TEA (177 mg, 1.75mmol, 243 μL, 8.0 eq) and T3P (416 mg, 654 μmol, 389 μL, 50% purity, 3.0eq) at 0° C., the reaction mixture was stirred at 0° C. for 1 hour.After completion, the reaction mixture was added saturated brine (10.0mL), then extracted with ethyl acetate (2×10 mL), the organic layer wasdried over Na₂SO₄, filtered and concentrated. The residue was purifiedby column chromatography (basic Al₂O₃, petroleum ether/ethyl acetate=3/1to ethyl acetate/methanol=20/1), the crude product was re-purified byprep-HPLC (column: Waters Xbridge 150*25 5μ; mobile phase: [water (0.05%ammonium hydroxide v/v)-ACN]; B %: 45%-75%, 10 min]; B %: 45%-75%, 10min), the obtained product was concentrated, and lyophilized. Titlecompound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile(50.9 mg, 81.0 μmol, 37% yield, 99% purity) was obtained as white solid.LCMS [ESI, M+1]: 622.

¹H NMR (400 MHz, chloroform-d) δ 7.76 (d, J=8.0 Hz, 1H), 7.62 (t, J=7.4Hz, 1H), 7.53 (d, J=7.2 Hz, 1H), 7.49-7.41 (m, 1H), 7.34 (t, J=7.8 Hz,1H), 7.26-7.18 (m, 1H), 5.55-5.33 (m, 1H), 5.30-5.07 (m, 2H), 5.01-4.66(m, 1H), 4.53-4.35 (m, 2H), 4.29-3.98 (m, 3H), 3.96-3.78 (m, 2H),3.73-3.33 (m, 3H), 3.32-2.98 (m, 5H), 2.94-2.71 (m, 2H), 2.68-2.53 (m,2H), 2.51 (d, J=2.8 Hz, 3H), 2.39-2.23 (m, 1H), 2.08-1.87 (m, 1H).

Example 575

2-[(2S)-4-[7-(8-Chloro-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile

Step A: tert-Butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.To a solution of [(3R)-1-methylpyrrolidin-3-yl]methanol (297 mg, 2.58mmol, 2.50 eq) in toluene (6.0 mL) was added t-BuONa (198 mg, 2.06 mmol,2.0 eq). The mixture was stirred at 0° C. for 0.5 hour. Then tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(600 mg, 1.03 mmol, 1.0 eq) was added to the above liquid. Afteraddition, the mixture was stirred at 0° C. for another 0.5 hour. Aftercompletion, water was added (20.0 mL) and the resulting mixtureextracted with ethyl acetate (3×10.0 mL). The organic layer was driedover Na₂SO₄, filtered and concentrated. The residue was purified byreverse phase flash (C18, 0.1% FA in water, 0-60% MeCN) to give thecompound tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(430 mg, 680 μmol, 66% yield) as yellow solid. LCMS [ESI, M+1]: 632.

¹H NMR (400 MHz, Chloroform-d) δ 7.75 (d, J=8.0 Hz, 1H), 7.61 (t, J=7.6Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 7.48-7.39 (m, 1H), 7.33 (t, J=7.6 Hz,1H), 7.26-7.15 (m, 1H), 4.67-4.55 (m, 1H), 4.50-4.35 (m, 1H), 4.27-4.17(m, 2H), 4.08-3.75 (m, 4H), 3.65-3.50 (m, 1H), 3.39-3.02 (m, 5H),3.00-2.86 (m, 1H), 2.81-2.64 (m, 4H), 2.62-2.46 (m, 4H), 2.35 (s, 3H),2.15-2.05 (m, 1H), 1.52 (s, 9H).

Step B:2-[(2S)-4-[7-(8-Chloro-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(400 mg, 632 μmol, 1.0 eq) in dioxane (2.0 mL) was added HCl·dioxane(4.0 M, 2.0 mL, 12.6 eq). The mixture was stirred at 15° C. for 1 hour.After completion, the reaction mixture was concentrated. The residue wasadjusted with saturated aqueous NaHCO₃ (10.0 mL) to pH˜7, and thenextracted with ethyl acetate (3×10.0 mL). The organic layer was driedover Na₂SO₄, filtered and concentrated to give the compound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(240 mg, 451 μmol, 71% yield) as yellow solid which was used for thenext step without further purification. LCMS [ESI, M+1]: 532.

Step C:2-[(2S)-4-[7-(8-Chloro-1-naphthyl)-2-[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(80.0 mg, 150 μmol, 1.0 eq), 2-fluoroprop-2-enoic acid (27.1 mg, 301μmol, 2.0 eq) and TEA (122 mg, 1.20 mmol, 167 μL, 8.0 eq) in ethylacetate (2.0 mL) was added T3P (287 mg, 451 umol, 268 μL, 50%, 4 purityin ethyl acetate, 3.0 eq). The mixture was stirred at 0° C. for 0.5hour. After completion, the reaction mixture was quenched with HCl (12.0M, 60.0 uL in 2.0 mL of water). The mixture was adjusted to pH˜8 withsaturated aqueous NaHCO₃ and extracted with ethyl acetate (3×10.0 mL).The combined organic layers were washed with brine (30.0 mL), dried overNa₂SO₄, filtered and concentrated. The residue was purified by prep-HPLC(column: Phenomenex Synergi C18 150*25*10 μm; mobile phase: [water(0.225% FA)-ACN]; B %: 25%-45%, 8 min), then concentrated. The aqueouslayer was adjusted with saturated aqueous NaHCO₃ to pH˜8 and extractedwith ethyl acetate (3×10.0 mL). The organic layer was dried over Na₂SO₄,filtered and concentrated under reduced pressure to give the titlecompound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile(35.9 mg, 57.5 μmol, 38% yield, 96.8% purity) as white solid. LCMS [ESI,M+1]: 604.

¹H NMR (400 MHz, Chloroform-d) δ 7.78-7.73 (d, J=8.4 Hz, 1H), 7.62 (t,J=7.2 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 7.49-7.40 (m, 1H), 7.34 (t, J=8.0Hz, 1H), 7.27-7.18 (m, 1H), 5.54-5.32 (m, 1H), 5.30-5.21 (m, 1H),5.04-4.75 (m, 1H), 4.48-4.36 (m, 1H), 4.27-4.17 (m, 2H), 4.16-3.96 (m,2H), 3.89-3.75 (m, 1H), 3.64-3.55 (m, 1H), 3.51-3.32 (m, 1H), 3.30-2.98(m, 4H), 2.96-2.67 (m, 4H), 2.66-2.46 (m, 4H), 2.37 (d, J=2.0 Hz, 3H),2.14-2.06 (m, 1H), 1.70-1.57 (m, 1H).

Example 576

2-[(2S)-4-[7-(8-Chloro-1-naphthyl)-2-[[(2R,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile

Step A: tert-Butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.To a solution of tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(300 mg, 516 μmol, 1 eq) in toluene (5.00 mL) was added t-BuONa (124 mg,1.29 mmol, 2.5 eq) and[(2R,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methanol (149 mg, 1.03 mmol,2 eq). The mixture was stirred at 0° C. for 1 hour. The reaction mixturewas diluted with water (20 mL) and extracted with ethyl acetate (50mL×3). The combined organic layers were washed with brine (20 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (SiO₂, ethylacetate/methanol=100/1 to 10:1). tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(200 mg, 265 μmol, 51% yield, 88% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 662.

Step B:2-[(2S)-4-[7-(8-Chloro-1-naphthyl)-2-[[(2R,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(200 mg, 302 μmol, 1 eq) in dioxane (1.00 mL) was added HCl/dioxane (4M, 1.13 mL, 1.00 eq). The mixture was stirred at 20° C. for 1 hour. Thereaction mixture was concentrated under vacuum and diluted with water(20 mL). The mixture was adjusted to pH=8 with saturated NaHCO₃ aqueoussolution and extracted with ethyl acetate (30 mL×3). The combinedorganic layers were washed with brine (20 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give the residue.2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(110 mg, 154.60 μmol, 70% yield, 79% purity) was obtained as a yellowsolid and used next step without purification. LCMS [ESI, M+1]: 562.

Step C:2-[(2S)-4-[7-(8-Chloro-1-naphthyl)-2-[[(2R,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(110 mg, 195 μmol, 1 eq) in ethyl acetate (1.00 mL) was added2-fluoroprop-2-enoic acid (35.3 mg, 391 μmol, 2 eq), T3P (374 mg, 587μmol, 349 μLL, 50% purity, 3 eq) and TEA (158 mg, 1.57 mmol, 218 μL, 8eq). The mixture was stirred at 0° C. for 0.5 hour. The reaction mixturewas diluted with water (20 mL) and extracted with ethyl acetate (30mL×3). The combined organic layers were washed with brine (20 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (SiO₂, ethylacetate/methanol=100/1 to 10/1) and further by prep-HPLC (column: WatersXbridge 150*25 5μ; mobile phase: [water (0.05% ammonium hydroxidev/v)-ACN]; B %: 45%-75%, 10 min). The desired fractions were collectedand lyophilized. Title compound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile(17 mg, 26.7 μmol, 14% yield, 99.8% purity) was obtained as a white gumLCMS [ESI, M+1]: 634.

¹H NMR (400 MHz, chloroform-d) δ=7.76 (d, J=8.4 Hz, 1H), 7.62 (t, J=7.6Hz, 1H), 7.53 (d, J=7.2 Hz, 1H), 7.49-7.40 (m, 1H), 7.34 (t, J=7.6 Hz,1H), 7.27-7.18 (m, 1H), 5.42 (d, J=49.2 Hz, 1H), 5.26 (dd, J=3.6, 16.8Hz, 1H), 4.91 (br s, 1H), 4.54-4.34 (m, 2H), 4.27-4.00 (m, 3H),3.96-3.77 (m, 2H), 3.67-3.54 (m, 1H), 3.51-3.37 (m, 1H), 3.37-2.96 (m,9H), 2.95-2.64 (m, 3H), 2.63-2.53 (m, 1H), 2.52-2.27 (m, 5H), 1.91-1.74(m, 1H).

Example 577

2-[(2S)-4-[7-(8-Chloro-1-naphthyl)-2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile

Step A: tert-Butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.To a solution of [(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methanol(300 mg, 2.06 mmol, 2.0 eq) and t-BuONa (149 mg, 1.55 mmol, 1.50 eq) intoluene (7.0 mL) was addedtert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(600 mg, 1.03 mmol, 1.0 eq). The mixture was stirred at 0° C. for 0.5hour. After completion, water was added (20.0 mL) and the resultingmixture extracted with ethyl acetate (3×10.0 mL). The organic layer wasdried over Na₂SO₄, filtered and concentrated. The residue was purifiedby reverse phase flash (C18, 0.1% FA in water, 0-60% MeCN) to give thecompound tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(450 mg, 652 μmol, 63% yield, 96% purity) as yellow solid. LCMS [ESI,M+1]: 662.

¹H NMR (400 MHz, Chloroform-d) δ 7.76 (br d, J=8.4 Hz, 1H), 7.61 (t,J=7.8 Hz, 1H), 7.52 (d, J=7.6 Hz, 1H), 7.48-7.40 (m, 1H), 7.35 (t, J=7.8Hz, 1H), 7.27-7.16 (m, 1H), 4.63-4.56 (m, 1H), 4.50-4.35 (m, 2H),4.23-4.15 (m, 1H), 4.12-3.91 (m, 4H), 3.90-3.75 (m, 1H), 3.65-3.53 (m,1H), 3.50-3.39 (m, 1H), 3.38-3.32 (m, 1H), 3.30 (d, J=2.0 Hz, 3H),3.28-3.06 (m, 3H), 3.02-2.85 (m, 2H), 2.83-2.64 (m, 2H), 2.62-2.52 (m,1H), 2.47 (d, J=2.8 Hz, 3H), 2.35-2.29 (m, 1H), 2.11-2.06 (m, 1H),2.03-1.91 (m, 1H), 1.52 (s, 9H).

Step B:2-[(2S)-4-[7-(8-Chloro-1-naphthyl)-2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(450 mg, 680 μmol, 1.0 eq) in dioxane (4.0 mL) was added HCl·dioxane (4M, 4.0 mL, 23.6 eq). The mixture was stirred at 15° C. for 0.5 hour.After completion, the reaction mixture was concentrated. The residue wasadjusted with saturated aqueous NaHCO₃ (10.0 mL) to pH˜7, and thenextracted with ethyl acetate (3×10.0 mL). The organic layer was driedover Na₂SO₄, filtered and concentrated to give2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(300 mg, crude) as yellow solid which was used for the next step withoutfurther purification. LCMS [ESI, M+1]: 562.

Step C:2-[(2S)-4-[7-(8-Chloro-1-naphthyl)-2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(90.0 mg, 160 μmol, 1.0 eq), 2-fluoroprop-2-enoic acid (28.8 mg, 320μmol, 2.0 eq) and TEA (130 mg, 1.28 mmol, 178 μL, 8.0 eq) in EA (3.0 mL)was added T3P (306 mg, 480 μmol, 286 μL, 50% purity, 3.0 eq). Themixture was stirred at 0° C. for 1 hour. After completion, water wasadded (10.0 mL) and the resulting mixture extracted with ethyl acetate(3×10.0 mL). The organic layer was dried over Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by prep-HPLC(column: Waters Xbridge 150*25 5μ; mobile phase: [water (0.05% ammoniumhydroxide v/v)-ACN]; B %: 50%-80%, 10 min) to give title compound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile(32.0 mg, 50.3 μmol, 31% yield, 99% purity) as white solid LCMS [ESI,M−41]: 635.

¹H NMR (400 MHz, Chloroform-d) δ 7.76 (d, J=8.4 Hz, 1H), 7.62 (t, J=7.6Hz, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.49-7.40 (m, 1H), 7.34 (t, J=7.8 Hz,1H), 7.26-7.17 (m, 1H), 5.54-5.32 (m, 1H), 5.26 (dd, J=3.6, 16.8 Hz,1H), 5.10-4.70 (m, 1H), 4.52-4.34 (m, 2H), 4.27-3.80 (m, 6H), 3.69-3.54(m, 1H), 3.50-3.37 (m, 2H), 3.30 (d, J=1.6 Hz, 3H), 3.28-3.02 (m, 4H),2.98-2.68 (m, 3H), 2.65-2.53 (m, 1H), 2.47 (d, J=2.4 Hz, 3H), 2.37-2.28(m, 1H), 2.13-2.03 (m, 1H), 2.02-1.90 (m, 1H).

Example 578

2-[(2S)-1-[(E)-4-Fluorobut-2-enoyl]-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

Step A: Benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 840 μmol, 1.00 eq) in toluene (10.0 mL) was added t-BuONa (202mg, 2.10 mmol, 2.50 eq) and[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methanol (224 mg, 1.68 mmol,2.00 eq). After stirred at 0° C. for 1 hour, the reaction mixture wasdiluted with water (20 mL) and extracted with ethyl acetate (50 mL×3).The combined organic layers were washed with brine (20 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (SiO₂, ethylacetate/methanol=100/1 to 10/1). Benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(340 mg, 502 μmol, 60% yield, 98% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 664.

Step B: 2-[(2S)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 301 μmol, 1.00 eq) in MeOH (15.0 mL) was added Pd/C (30.0 mg,10% purity) and NH₃/MeOH (5.00 mL, 20% purity) under N₂. The suspensionwas degassed under vacuum and purged with H₂ several times. The mixturewas stirred under H₂ (15 psi) at 15° C. for 0.5 hour. The catalyst wasfiltered off. The filtrate was concentrated under vacuum.2-[(2S)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(159 mg, 294 μmol, 98% yield, 98% purity) was obtained as a yellow solidand used next step directly without purification. LCMS [ESI, M+1]: 530.

Step C:2-((2S)-1-[(E)-4-Fluorobut-2-enoyl]-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(140 mg, 264 μmol, 1.00 eq) and (E)-4-fluorobut-2-enoic acid (82.5 mg,793 μmol, 3.00 eq) in ethyl acetate (2.00 mL) was added TEA (160 mg,1.59 mmol, 220 μL, 6.00 eq) and T3P (505 mg, 793 μmol, 472 μL, 50%purity, 3.00 eq) at −70° C. The mixture was stirred at −70° C. for 1hour. The reaction mixture was quenched with HCl (12 N, 130 μL in 2 mLof water) at −70° C. The mixture was warmed to 0° C. and basified withsaturated NaHCO₃ aqueous solution to pH=8 and extracted with ethylacetate (20 mL×3). The combined organic layers were washed with brine(10 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give the residue. The residue was purified by prep-HPLC(column: Waters Xbridge 150*25 5μ; mobile phase: [water (0.05% ammoniumhydroxide v/v)-ACN]; B %: 45%-75%, 10 min). The desired fractions werecollected and lyophilized. Title compound2-[(2S)-1-[(E)-4-fluorobut-2-enoyl]-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(34.5 mg, 55.8 umol, 21% yield, 99.7% purity) was obtained as a whitesolid. LCMS [ESI, M+1]: 616.

¹H NMR (400 MHz, chloroform-d) δ=7.74-7.62 (m, 2H), 7.46-7.31 (m, 2H),7.27-7.17 (m, 2H), 7.09-6.93 (m, 1H), 6.59 (d, J=15.2 Hz, 1H), 5.30-4.51(m, 4H), 4.48-4.35 (m, 1H), 4.30-3.66 (m, 6H), 3.63-3.34 (m, 3H),3.24-2.96 (m, 5H), 2.92 (s, 3H), 2.87-2.53 (m, 4H), 2.50 (d, J=4.4 Hz,3H), 2.40-2.22 (m, 1H), 2.10-1.86 (m, 1H) (m, 3H).

Example 579

2-[(2S)-1-[(E)-4-Fluorobut-2-enoyl]-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

Step A: Benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 841 μmol, 1 eq) in toluene (10 mL) was added t-BuONa (242 mg,2.52 mmol, 3 eq) and [(2R)-1-methylpyrrolidin-2-yl]methanol (194 mg,1.68 mmol, 2 eq) at 0° C. The mixture was stirred at 0° C. for 0.5 hour.The reaction mixture was diluted with water (20 mL) and extracted withethyl acetate (20 mL×3). The combined organic layers were washed withbrine (20 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by columnchromatography (SiO₂, Ethyl acetate/MeOH=100/1 to 10/1). benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(240 mg, 338 μmol, 40%0 yield, 91% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 646.

Step B:2-[(2S)-4-[7-(8-Methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(240 mg, 372 μmol, 1 eq) in MeOH (15 mL) was added Pd/C (30 mg, 10%purity) and NH₃·MeOH (5 mL, 20% purity) under N₂. The suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred under H₂ (15 psi) at 15° C. for 1 hour. The catalyst wasfiltered off. The filtrate was concentrated under vacuum.2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(180 mg, 352 μmol, 95% yield) was obtained as a yellow solid and usednext step directly without purification. LCMS [ESI, M+1]: 512.

Step C:2-[(2S)-1-[(E)-4-Fluorobut-2-enoyl]-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(100 mg, 195 umol, 1 eq) and (E)-4-fluorobut-2-enoic acid (40.7 mg, 391umol, 2 eq) in EtOAc (2 mL) was added TEA (79.1 mg, 782 umol, 109 uL, 4eq) and T3P (249 mg, 391 umol, 232 uL, 50% purity in EtOAc, 2 eq) at−70° C. The mixture was stirred at −70° C. for 1 hour. The reactionmixture was quenched with HCl (60 uL (12 M) in 2 mL of water). Themixture was adjusted pH=8 with saturated NaHCO₃ aqueous solution andextracted with ethyl acetate (20 mL×3). The combined organic layers werewashed with brine (10 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give the residue. The residue was purified byprep-HPLC (column: Luna C18 150*25 5 u; mobile phase: [water (0.225%FA)-ACN]; B %: 25%-45%, 7.8 min) and further purified by prep-HPLC(column: Waters Xbridge 150*25 5 u; mobile phase: [water (0.05% ammoniahydroxide v/v)-ACN]; B %: 52%-79%, 10 min). The desired fractions werecollected and lyophilized. Title compound2-[(2S)-1-[(E)-4-fluorobut-2-enoyl]-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(16.6 mg, 27.7 umol, 14% yield, 99.6% purity) was obtained as a yellowgum. LCMS [ESI, M+1]: 598.

¹H NMR (400 MHz, chloroform-d) δ=7.72-7.62 (m, 2H), 7.45-7.32 (m, 2H),7.27-7.16 (m, 2H), 7.07-6.93 (m, 1H), 6.60 (d, J=15.6 Hz, 1H), 5.26-4.51(m, 3H), 4.39 (s, 1H), 4.31-3.33 (m, 9H), 3.27-2.97 (m, 5H), 2.92 (s,3H), 2.87-2.76 (m, 1H), 2.65 (m, 2H), 2.49 (br d, J=4.6 Hz, 3H), 2.29(m, 1H), 2.15-1.96 (m, 1H), 1.92-1.67 (m, 3H).

Example 580

2-[(2S)-1-[(E)-4-fluorobut-2-enoyl]-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

Step A: Benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 841 μmol, 1 eq) in toluene (10 mL) was added t-BuONa (242 mg,2.52 mmol, 3 eq) and [(2R)-1-methylpyrrolidin-2-yl]methanol (194 mg,1.68 mmol, 2 eq) at 0° C. The mixture was stirred at 0° C. for 0.5 hour.The reaction mixture was diluted with water (20 mL) and extracted withethyl acetate (20 mL×3). The combined organic layers were washed withbrine (20 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by columnchromatography (SiO₂, ethyl acetate/MeOH=100/1 to 10/1). Benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(240 mg, 338 μmol, 40% yield, 91% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 646.

Step B:2-[(2S)-4-[7-(8-Methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(240 mg, 372 μmol, 1 eq) in MeOH (15 mL) was added Pd/C (30 mg, 10%purity) and NH₃·MeOH (5 mL, 20% purity) under N₂. The suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred under H₂ (15 psi) at 15° C. for 1 hour. The catalyst wasfiltered off. The filtrate was concentrated under vacuum.2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(180 mg, 352 μmol, 95% yield) was obtained as a yellow solid and usednext step directly without purification. LCMS [ESI, M+1]: 512.

Step C:2-[(2S)-1-[(E)-4-Fluorobut-2-enoyl]-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(100 mg, 195 μmol, 1 eq) and (E)-4-fluorobut-2-enoic acid (40.7 mg, 391umol, 2 eq) in EtOAc (2 mL) was added TEA (79.1 mg, 782 μmol, 109 μL, 4eq) and T3P (249 mg, 391 μmol, 232 μL, 50% purity in EtOAc, 2 eq) at−70° C. The mixture was stirred at −70° C. for 1 hour. The reactionmixture was quenched with HCl (60 μL (12 M) in 2 mL of water). Themixture was adjusted pH=8 with saturated NaHCO₃ aqueous solution andextracted with ethyl acetate (20 mL×3). The combined organic layers werewashed with brine (10 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give the residue. The residue was purified byprep-HPLC (column: Luna C18 150*25 5μ; mobile phase: [water (0.225%FA)-MeCN]; 13%: 25%-45%, 7.8 min) and further purified by prep-HPLC(column: Waters Xbridge 150*25 5μ; mobile phase: [water (0.05% ammoniumhydroxide v/v)-MeCN]; B %: 52%-79%, 10 min). The desired fractions werecollected and lyophilized. Title compound2-[(2S)-1-[(E)-4-fluorobut-2-enoyl]-4-[7-(8-methyl-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(16.6 mg, 27.7 μmol, 14% yield, 99.6% purity) was obtained as a yellowgum. LCMS [ESI, M+1]: 628.

¹H NMR (400 MHz, chloroform-d) δ=7.73-7.62 (m, 2H), 7.45-7.32 (m, 2H),7.27-7.17 (m, 2H), 7.08-6.93 (m, 1H), 6.60 (br d, J=16.0 Hz, 1H),5.26-4.54 (m, 3H), 4.40 (m, 1H), 4.31-3.69 (m, 7H), 3.61-3.36 (m, 3H),3.30 (d, J=2.0 Hz, 3H), 3.24-2.96 (m, 4H), 2.92 (s, 3H), 2.91-2.55 (m,4H), 2.47 (d, J=4.8 Hz, 3H), 2.37-2.26 (m, 1H), 2.13-2.03 (m, 1H),2.01-1.89 (m, 1H).

Example 581

2-[(2S)-1-[(E)-4-fluorobut-2-enoyl]-4-[7-(8-methyl-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

Step A: Benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(450 mg, 757 umol, 1 eq) and [(3R)-1-methylpyrrolidin-3-yl]methanol (131mg, 1.13 mmol, 1.5 eq) in toluene (9 mL) was added t-BuONa (145 mg, 1.51mmol, 2 eq). The mixture was stirred at 0° C. for 10 minutes. Uponcompletion, water was added (15 mL) and the resulting mixture extractedwith ethyl acetate (30 mL×2). The organic layers were dried over Na₂SO₄,filtered and concentrated under vacuum. The residue was purified byreverse phase flash [water (0.1% FA)/acetonitrile]. The desiredfractions were collected and neutralized with NaHCO₃, concentrated undervacuum to remove MeCN and extracted with EtOAc (2×50 mL). The organiclayers were dried over Na₂SO₄ and concentrated under vacuum to givebenzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(300 mg, 455 μmol, 60% yield, 98% purity) as a pink solid.

¹H NMR (400 MHz, chloroform-d) δ=7.73-7.60 (m, 2H), 7.45-7.37 (m, 5H),7.37-7.30 (m, 2H), 7.26-7.16 (m, 2H), 5.21 (s, 2H), 4.68 (br s, 1H),4.30-3.78 (m, 7H), 3.59-3.29 (m, 2H), 3.25-2.94 (m, 4H), 2.91 (s, 3H),2.82-2.62 (m, 4H), 2.62-2.53 (m, 2H), 2.53-2.42 (m, 2H), 2.35 (s, 3H),2.05 (s, 1H), 1.66-1.51 (m, 1H).

Step B: 2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(3R)-1-methylpyrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(300 mg, 465 μmol, 1 eq) in MeOH (4 mL) was added Pd/C (150 mg, 10%purity), NH₃/MeOH (4 mL, 20% purity) under N₂. The suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred under H₂ (15 psi) at 15° C. for 1 hour. Upon completion, themixture was filtered and the filtrate was concentrated under vacuum togive 2-[(2S)-4-(7-(8-methyl-1-naphthyl)-2-[[(3R)-1-methylpyrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(210 mg, 369 μmol, 80% yield, 90% purity) as a pink solid which was useddirectly in the next step without further purification. LCMS [ESI, M+1]:512.

Step C:2-[(2S)-1-[(E)-4-fluorobut-2-enoyl]-4-[7-(8-methyl-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(70 mg, 137 μmol, 1 eq), TEA (41.5 mg, 410 μmol, 57.1 μL, 3 eq) and(E)-4-fluorobut-2-enoic acid (28.5 mg, 274 μmol, 2 eq) in EtOAc (2 mL)was added T3P (131 mg, 205 μmol, 122 μL, 50% purity in EtOAc, 1.5 eq) at0° C. The mixture was stirred at 0° C. for 0.5 hour. Upon completion,the reaction mixture was quenched with 1 M HCl (0.4 mL) at −40° C. andstirred until no ice remained. The separated aqueous layer wasconcentrated under vacuum. The residue was purified by prep-HPLC(column: Phenomenex Synergi C18 150*30 mm*4 μm; mobile phase: [water(0.225% FA)-MeCN], B %: 20%-50%, 10 min). The desired fractions werecollected and lyophilized to give title compound2-[(2S)-1-[(E)-4-fluorobut-2-enoyl]-4-[7-(8-methyl-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(13.7 mg, 20.8 μmol, 15% yield, 97.7% purity, FA) as a gray solid. LCMS[ESI, M+1]: 598.

¹H NMR (400 MHz, chloroform-d) δ=7.66-7.59 (m, 1H), 7.59-7.51 (m, 1H),7.32 (td, J=7.6, 11.6 Hz, 1H), 7.26 (t, J=7.6 Hz, 1H), 7.19-7.07 (m,2H), 7.00-6.83 (m, 1H), 6.52 (br d, J=14.8 Hz, 1H), 5.21-4.31 (m, 3H),4.29-3.96 (m, 3H), 3.94-3.53 (m, 7H), 3.45 (br d, J=6.8 Hz, 4H),3.15-2.88 (m, 7H), 2.84 (s, 3H), 2.81-2.74 (m, 1H), 2.61-2.47 (m, 2H),2.18 (br s, 1H), 1.85 (br s, 1H).

Example 582

2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4-fluorobut-2-enoyl)piperazin-2-yl)acetonitrile

2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4-fluorobut-2-enoylpiperazin-2-yl)acetonitrile.To a solution of2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(180 mg, 327 μmol, 1.0 eq) and (E)-4-fluorobut-2-enoic acid (102 mg, 982μmol, 3.0 eq) was added TEA (265 mg, 2.62 mmol, 364 μL, 8.0 eq) and T3P(833 mg, 1.31 mmol, 778 μL, 50% purity, 4.0 eq), the reaction mixturewas stirred at −65° C. for 1 hour. After completion, the reactionmixture was quenched with 2 N HCl to pH˜7 at −65° C., then the organiclayer was separated, the aqueous phase was extracted with ethyl acetate(2×10 mL), the combined organic layer was dried over Na₂SO₄, filteredand concentrated. The residue was purified column chromatography (basicAl₂O₃, petroleum ether/ethyl acetate=3/1 to ethylacetate/methanol=20/1), the crude product was re-purified by prep-HPLC(column: Xtimate C18 150*25 mm*5 μm; mobile phase: [water (0.05%ammonium hydroxide v/v)-MeCN]; B %: 50%-80%, 8 min), the obtainedproduct was concentrated, and lyophilized. Title compound2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4-fluorobut-2-enoyl)piperazin-2-yl)acetonitrile(72.2 mg, 113 μmol, 34% yield, 99% purity) was obtained as white solid.LCMS [ESI, M+1]: 637.

¹H NMR (400 MHz, chloroform-d) δ 7.79-7.73 (m, 1H), 7.62 (t, J=7.0 Hz,1H), 7.53 (d, J=7.2 Hz, 1H), 7.49-7.41 (m, 1H), 7.34 (t, J=7.6 Hz, 1H),7.27-7.18 (m, 1H), 7.08-6.93 (m, 1H), 6.59 (br d, J=14.8 Hz, 1H),5.29-5.03 (m, 3H), 4.54-4.52 (m, 1H), 4.50-4.35 (m, 2H), 4.30-3.78 (m,5H), 3.76-3.35 (m, 3H), 3.32-2.96 (m, 5H), 2.91-2.54 (m, 4H), 2.51 (d,J=3.2 Hz, 3H), 2.39-2.23 (m, 1H), 2.08-1.86 (m, 1H).

Example 583

2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-fluorobut-2-enoyl]piperazin-2-yl]acetonitrile

2-[(2S)-4-[7-(8-Chloro-1-naphthyl)-2-1[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-fluorobut-2-enoyl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(150 mg, 267 μmol, 1.0 eq), (E)-4-fluorobut-2-enoic acid (55.6 mg, 534μmol, 2.0 eq) and TEA (108 mg, 1.07 mmol, 149 μL, 4.0 eq) in ethylacetate (4.0 mL) was added T3P (340 mg, 534 μmol, 317 μL, 50% purity,2.0 eq). The mixture was stirred at −70° C. for 1 hour. Aftercompletion, the reaction mixture was quenched with HCl (12 M, 60.0 μL in2.0 mL of water). The mixture was adjusted to pH˜8 with saturated NaHCO₃aqueous solution and extracted with ethyl acetate (3×20.0 mL). Thecombined organic layers were washed with saturated brine (60.0 mL),dried over Na₂SO₄, filtered and concentrated. The residue was purifiedby prep-HPLC (column: Xtimate C18 150*25 mm*5 um; mobile phase: [water(0.05% ammonium hydroxide v/v)-MeCN]; B %: 50%-80, 8 min) to give titlecompound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-fluorobut-2-enoyl]piperazin-2-yl]acetonitrile(39.6 mg, 60.9 μmol, 23% yield, 99% purity) as white solid. LCMS [ESI,M+1]: 619.

¹H NMR (400 MHz, Chloroform-d) δ 7.76 (br d, J=8.0 Hz, 1H), 7.62 (t,J=7.6 Hz, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.49-7.40 (m, 1H), 7.34 (t, J=8.0Hz, 1H), 7.27-7.17 (m, 1H), 7.08-6.94 (m, 1H), 6.67-6.54 (m, 1H),5.25-5.03 (m, 2H), 4.80-4.60 (m, 1H), 4.48-4.34 (m, 2H), 4.21-3.77 (m,5H), 3.65-3.55 (m, 1H), 3.51-3.37 (m, 1H), 3.31-2.97 (m, 5H), 2.88-2.54(m, 4H), 2.48 (d, J=3.6 Hz, 3H), 2.34-2.24 (m, 1H), 2.11-2.01 (m, 1H),1.90-1.69 (m, 3H).

Example 584

2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-fluorobut-2-enoyl]piperazin-2-yl]acetonitrile

2-[(2S)-4-[7-(8-Chloro-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-fluorobut-2-enoyl]piperazin-2-yl]acetonitrile

To a solution of2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(100 mg, 188 μmol, 1.0 eq), (E)-4-fluorobut-2-enoic acid (39.1 mg, 376μmol, 2.0 eq) and TEA (95.1 mg, 940 μmol, 131 μL, 5.0 eq) in ethylacetate (3.0 mL) was added T3P (179 mg, 282 μmol, 168 μL, 50% purity,1.50 eq). The mixture was stirred at 0° C. for 0.5 hour. Aftercompletion, the reaction mixture was quenched with HCl (12 M, 5.0 eq) at−40° C. The mixture was adjusted to pH˜8 with saturated aqueous NaHCO₃and extracted with ethyl acetate (3×10.0 mL). The combined organiclayers were washed with brine (30.0 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by prep-HPLC (column: PhenomenexSynergi C18 150*25*10 μm; mobile phase: [water (0.225% FA)-MeCN]; B %:30-50%, 8 min) to give the title compound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-fluorobut-2-enoyl]piperazin-2-yl]acetonitrile(15.7 mg, 24.9 μmol, 13% yield, 98% purity) as a yellow solid. LCMS[ESI, M+1]: 619.

¹H NMR (400 MHz, Chloroform-d) δ 7.76 (d, J=8.4 Hz, 1H), 7.65-7.59 (m,1H), 7.56-7.49 (m, 1H), 7.48-7.40 (m, 1H), 7.34 (t, J=7.6 Hz, 1H),7.26-7.18 (m, 1H), 7.08-6.92 (m, 1H), 6.74-6.46 (m, 1H), 5.25-4.95 (m,3H), 4.75-4.55 (m, 1H), 4.47-4.36 (m, 1H), 4.35-4.26 (m, 2H), 4.14-3.92(m, 2H), 3.91-3.76 (m, 1H), 3.64-3.55 (m, 1H), 3.53-3.35 (m, 1H),3.33-3.04 (m, 7H), 3.03-2.72 (m, 4H), 2.67 (d, J=4.0 Hz, 3H), 2.64-2.51(m, 1H), 2.31-2.19 (m, 1H), 1.98-1.85 (m, 1H).

Example 585

2-((S)-4-(2-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(8-chloronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4-fluorobut-2-enoyl)piperazin-2-yl)acetonitrile

Step A: tert-Butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.To a mixture of3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propan-1-ol (150 mg, 954μmol, 1.85 eq) in toluene (3.0 mL) was added t-BuONa (99.2 mg, 1.03mmol, 2.0 eq) in portions at 0° C., after stirring at 0° C. for 0.5hour, tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(300 mg, 516 μmol, 1.0 eq) was added to the mixture, and stirred at 0°C. for 0.5 hour. After completion, water was added (15 mL), and theresulting mixture extracted with ethyl acetate (2×10 mL), the combinedorganic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by reverse phase flash (C18, 0.1% TFA in water,30%-50% MeCN), the obtained product was adjusted with NaHCO₃ solid topH˜8, then concentrated, the aqueous phase was extracted with ethylacetate (2×15 mL), the organic layer was washed with saturated brine(1×20 mL), dried over Na₂SO₄, filtered and concentrated. The producttert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(180 mg, 267 μmol, 52% yield, 100% purity) was obtained as light yellowsolid. LCMS [ESI, M+1]: 674.

¹H NMR (400 MHz, chloroform-d) δ 7.76 (br d, J=8.4 Hz, 1H), 7.61 (t,J=7.6 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 7.48-7.40 (m, 1H), 7.34 (t, J=7.8Hz, 1H), 7.26-7.17 (m, 1H), 4.66-4.54 (m, 1H), 4.50-4.29 (m, 4H),4.08-3.77 (m, 5H), 3.65-3.54 (m, 2H), 3.51-3.44 (m, 1H), 3.39-3.31 (m,1H), 3.29-3.02 (m, 4H), 3.00-2.87 (m, 2H), 2.84-2.46 (m, 6H), 1.99-1.82(m, 3H), 1.52 (s, 9H).

Step B:2-[(2S)-4-[7-(8-Chloro-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(150 mg, 222 μmol, 1.0 eq) in dioxane (1.0 mL) was added 4 N HCl·dioxane(1.0 mL), the reaction mixture was stirred at 15° C. for 1 hour. Aftercompletion, the reaction mixture was concentrated, added dichloromethane(10 mL), then washed with saturated aqueous Na₂CO₃ (1×10 mL), theorganic layer was dried over Na₂SO₄, filtered and concentrated. Theproduct2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(100 mg, 172 μmol, 77% yield, 98% purity) was obtained as brown oil.LCMS [ESI, M+1]: 574.

Step C:2-((S)-4-(2-(3-((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(8-chloronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4-fluorobut-2-enoyl)piperazin-2-yl)acetonitrile.To a solution of2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(90.0 mg, 157 μmol, 1.0 eq) and (E)-4-fluorobut-2-enoic acid (48.9 mg,470 μmol, 3.0 eq) in ethyl acetate (1.0 mL) was added TEA (127 mg, 1.25mmol, 175 μL, 8.0 eq) and T3P (399 mg, 627 μmol, 373 μL, 50% purity, 4.0eq) in portions at −65° C., the reaction mixture was stirred at −65° C.for 1 hour. After completion, the reaction mixture was quenched with 2 NHCl to pH˜7 at −65° C., then the organic layer was separated, theaqueous phase was extracted with ethyl acetate (2×10 mL), the combinedorganic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was purified column chromatography (basic Al₂O₃, petroleumether/ethyl acetate=3/1 to ethyl acetate/methanol=20/1), the crudeproduct was re-purified by prep-HPLC (column: Xtimate C18 150*25 mm*5μm; mobile phase: [water (0.05% ammonium hydroxide v/v)-MeCN]; B %:44%-74%, 8 min), the obtained product was concentrated, and lyophilized.Title compound2-((S)-4-(2-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(8-chloronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4-fluorobut-2-enoyl)piperazin-2-yl)acetonitrile(10.6 mg, 16.0 μmol, 10% yield, 99% purity) was obtained as white solid.LCMS [ESI, M+1]: 660.

¹H NMR (400 MHz, chloroform-d) δ 7.76 (br d, J=8.4 Hz, 1H), 7.62 (t,J=7.4 Hz, 1H), 7.53 (d, J=7.2 Hz, 1H), 7.49-7.41 (m, 1H), 7.34 (t, J=7.8Hz, 1H), 7.26-7.18 (m, 1H), 7.09-6.93 (m, 1H), 6.60 (br d, J=14.0 Hz,1H), 5.26-5.01 (m, 2H), 4.76-7.54 (m, 1H), 4.52-4.29 (m, 4H), 4.19-3.97(m, 3H), 3.95-3.69 (m, 2H), 3.66-3.37 (m, 4H), 3.33-2.99 (m, 4H),2.97-2.67 (m, 5H), 2.65-2.48 (m, 2H), 2.01-1.90 (m, 2H), 1.90-1.82 (m,1H), 1.76-1.69 (m, 1H).

Example 586

2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-fluorobut-2-enoyl]piperazin-2-yl]acetonitrile

Step A: tert-Butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]2-(cyanomethyl)piperazine-1-carboxylate.To a solution of [(2R)-1-methylpyrrolidin-2-yl]methanol (99.1 mg, 860μmol, 2.30 eq) in toluene (5.0 mL) was added t-BuONa (66.2 mg, 688 μmol,2.0 eq) and tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(200 mg, 344 μmol, 1.0 eq) in portions. The mixture was stirred at 0° C.for 0.5 hour. After completion, water was added (20.0 mL) and theresulting mixture extracted with ethyl acetate (3×10.0 mL). The organiclayer was dried over Na₂SO₄, filtered and concentrated. The residue waspurified by reverse phase flash (C18, 0.1% FA in water, 0-60% MeCN) togive the compound tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]2-(cyanomethyl)piperazine-1-carboxylate(200 mg, 313 μmol, 91% yield, 99% purity) as yellow solid. LCMS [ESI,M+1]: 632.

¹H NMR (400 MHz, Chloroform-d) δ 7.77-7.73 (m, 1H), 7.61 (t, J=7.6 Hz,1H), 7.54-7.50 (m, 1H), 7.49-7.39 (m, 1H), 7.33 (t, J=7.6 Hz, 1H),7.27-7.16 (m, 1H), 4.67-4.56 (m, 1H), 4.47-4.35 (m, 2H), 4.23-4.15 (m,1H), 4.09-3.89 (m, 3H), 3.88-3.77 (m, 1H), 3.63-3.53 (m, 1H), 3.41-3.30(m, 1H), 3.22-3.03 (m, 4H), 3.01-2.85 (m, 1H), 2.74-2.67 (m, 2H),2.63-2.51 (m, 2H), 2.49 (d, J=4.4 Hz, 3H), 2.36-2.25 (m, 1H), 2.11-2.05(m, 1H), 1.90-1.74 (m, 3H), 1.52 (s, 9H).

Step B:2-[(2S)-4-[7-(8-Chloro-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(200 mg, 316 μmol, 1.0 eq) in dioxane (3.0 mL) was added HCl·dioxane(4.0 M, 3.0 mL, 37.9 eq). The mixture was stirred at 15° C. for 0.5hour. After completion, the reaction mixture was concentrated. Theresidue was adjusted with saturated aqueous NaHCO₃ (10.0 mL) to pH˜7,and then extracted with ethyl acetate (3×10.0 mL). The organic layer wasdried over Na₂SO₄, filtered and concentrated to give the compound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(150 mg, crude) as yellow solid. The product was used for the next stepwithout further purification. LCMS [ESI, M+1]: 532.

Step C:2-[(2S)-4-[7-(8-Chloro-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-fluorobut-2-enoyl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(100 mg, 188 μmol, 1.0 eq) and (E)-4-fluorobut-2-enoic acid (39.1 mg,376 μmol, 2.0 eq) in ethyl acetate (2.0 mL) was added TEA (76.1 mg, 752μmol, 105 μL, 4.0 eq) and T3P (239 mg, 376 μmol, 224 μL, 50% purity, 2.0eq) at −70° C. The mixture was stirred at −70° C. for 1 hour. Aftercompletion, the reaction mixture was quenched with HCl (12.0 M, 60.0 μLin 2.0 mL of water). The mixture was adjusted to pH=8 with saturatedaqueous NaHCO₃ and extracted with ethyl acetate (3×10.0 mL). Thecombined organic layers were washed with brine (30.0 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give theresidue. The residue was purified by prep-HPLC (column: Xtimate C18150*25 mm*5 μm; mobile phase: [water (0.05% ammonium hydroxidev/v)-MeCN]; B %: 598%-89%, 8 min) to give the title compound2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-fluorobut-2-enoyl]piperazin-2-yl]acetonitrile(13.97 mg, 22.2 μmol, 12% yield, 98.4% purity) as white solid. LCMS[ESI, M+1]: 619.

¹H NMR (400 MHz, Chloroform-d) δ 7.76 (br d, J=8.0 Hz, 1H), 7.62 (t,J=7.6 Hz, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.49-7.40 (m, 1H), 7.34 (t, J=8.0Hz, 1H), 7.27-7.17 (m, 1H), 7.08-6.94 (m, 1H), 6.67-6.54 (m, 1H),5.25-5.03 (m, 2H), 4.80-4.60 (m, 1H), 4.48-4.34 (m, 2H), 4.21-3.77 (m,5H), 3.65-3.55 (m, 1H), 3.51-3.37 (m, 1H), 3.31-2.97 (m, 5H), 2.88-2.54(m, 4H), 2.48 (d, J=3.6 Hz, 3H), 2.34-2.24 (m, 1H), 2.11-2.01 (m, 1H),1.90-1.69 (m, 3H).

Example 587

N-((E)-4-((S)-2-(Cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-4-oxobut-2-en-1-yl)-N-methylacetamide

Step A: Ethyl (E)-4-(N-methylacetamido)but-2-enoate: Ethyl(E)-4-acetamidobut-2-enoate (140 mg, 0.818 mmol) was diluted with DMF (4mL) followed by the addition of NaH (21.6 mg, 0.900 mmol) and MeI (56.2μl, 0.900 mmol). After stirring for 12 hours, the reaction was dilutedwith ethyl acetate and saturated sodium bicarbonate. The layers wereseparated and the organic layer was dried over MgSO₄, filtered andconcentrated. The material was purified on silica gel eluting with10-70% ethyl acetate/hexanes to afford ethyl(E)-4-(N-methylacetamido)but-2-enoate (120 mg, 0.648 mmol, 79.2% yield).

Step B: (E)-4-N-methylacetamido)but-2-enoic acid: Ethyl(E)-4-(N-methylacetamido)but-2-enoate (20 mg, 0.11 mmol) was dilutedwith methanol (1 mL) followed by the addition of NaOH (270 μl, 0.54mmol). After stirring for 4 hours, the reaction was diluted with 2N HClto pH˜4 and the aqueous layer extracted with ethyl acetate. The ethylacetate was dried over MgSO₄, filtered and concentrated to afford(E)-4-(N-methylacetamido)but-2-enoic acid (15 mg, 0.095 mmol, 88%yield).

Step C:N-((E)-4-((S)-2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)4-oxobut-2-en-1-yl)-N-methylacetamide:2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(20 mg, 0.039 mmol) was diluted with DMF followed by the addition ofDIEA (13.65 μl, 0.07817 mmol). (E)-4-(N-methylacetamido)but-2-enoic acid(9.83 mg, 0.0625 mmol) was added followed by the addition of1-Propanephosphonic acid cyclic anhydride (39.6 μl, 0.0664 mmol). Afterstirring for 12 hours, the reaction was diluted with ethyl acetate andsaturated sodium bicarbonate. The layers were separated and the ethylacetate was dried over MgSO₄, filtered and concentrated. The materialwas purified on silica gel eluting with 10% methanol/DCM (1% NH₄OH) toaffordN-((E)-4-((S)-2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-4-oxobut-2-en-1-yl)-N-methylacetamide(2.1 mg, 0.0032 mmol, 8.2% yield). ESI+APCI MS m/z 651.4 [M+H]⁺.

Example 588

2-((S)-4-(7-(8-Bromonaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

Step A: Benzyl(S)-4-(7-(8-bromonaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:Benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(140 mg, 0.277 mmol), 1,8-dibromonaphthalene (238 mg, 0.831 mmol),Pd₂(dba)₃ (25.4 mg, 0.0277 mmol), Cs₂CO₃ (451 mg, 1.38 mmol) andXANTPHOS (32.0 mg, 0.0554 mmol) were diluted with toluene (111 μl, 0.277mmol). The reaction was purged with argon, sealed and heated to 110° C.while stirring for 12 hours. The reaction was allowed to cool anddiluted with ethyl acetate and water. The layers were separated and theethyl acetate was dried over MgSO₄, filtered and concentrated. Thematerial was purified on silica gel eluting with 1-10%, methanol/DCM (1%NH₄OH) to afford benzyl(S)-4-(7-(8-bromonaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethylpiperazine-1-carboxylate (80 mg, 0.113 mmol, 40.7% yield).

Step B:2-((S)-4-(7-(8-Bromonaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:Benzyl(S)-4-(7-(8-bromonaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(80 mg, 0.11 mmol) was diluted with TFA (2 mL), placed under nitrogenand heated to 900° C. After stirring for 2 hours, the reaction wascooled and concentrated. The material was diluted with DCM and washedwith saturated sodium bicarbonate. The DCM was dried over MgSO₄,filtered and concentrated. The material was purified on silica geleluting with 10% methanol/DCM (1% NH₄OH) to afford2-((S)-4-(7-(8-bromonaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(23 mg, 0.040 mmol, 35% yield).

Step C:2-((S)-4-(7-(8-Bromonaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile:2-((S)-4-(7-(8-bromonaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(23 mg, 0.040 mmol) was diluted with DMF (350 μL) followed by theaddition of DIEA (22 μl, 0.13 mmol) and 2-fluoroacrylic acid (5.4 mg,0.060 mmol). 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane2,4,6-trioxide (25 mg, 0.040 mmol) was added and the reaction wasstirred for 12 hours at room temperature. The reaction was diluted withethyl acetate and saturated sodium bicarbonate. The layers wereseparated and the ethyl acetate was dried over MgSO₄, filtered andconcentrated. The material was purified on silica gel eluting with 10%methanol/DCM (1% NH₄OH) to afford2-((S)-4-(7-(8-bromonaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile(9 mg, 0.014 mmol, 35% yield). ESI+APCI MS m/z 650.2 [M+H]⁺.

Example 589

2-((S)-1-(2-Fluoroacryloyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(8-(trifluoromethyl)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A:2-((S)-1-(2-Fluoroacryloyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(8-(trifluoromethyl)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:2-((S)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(8-(trifluoromethyl)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(24 mg, 0.042 mmol) was diluted with DMF (400 μL), DIEA (19 μl, 0.11mmol) was added followed by the addition of 2-fluoroacrylic acid (6.1mg, 0.068 mmol) and the addition of2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (30 μl,0.047 mmol). The reaction was stirred at ambient temperature for 10hours. The reaction was poured into a 5% sodium bicarbonate solution andextracted twice with ethyl acetate. The ethyl acetate was washed withwater, brine, dried over MgSO₄, filtered and concentrated. The materialwas purified on silica gel eluting with 1-10% methanol/DCM (1% NH₄OH) toafford2-((S)-1-(2-fluoroacryloyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(8-(trifluoromethyl)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(5 mg, 0.0078 mmol, 18% yield). ESI+APCI MS m/z 638.3 [M+H]⁺.

Example 590

2-((S)-4-(7-(8-Cyclopropylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

Step A: Benzyl(S)-2-(cyanomethyl)-4-(7-(8-cyclopropylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:Benzyl(S)-4-(7-(8-bromonaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(30 mg, 0.042 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (14 mg, 0.017 mmol) were diluted withcyclopropylzine bromide (253 μl, 0.13 mmol). The reaction was purgedwith argon, sealed and heated to 90° C. After stirring for 12 hours, thereaction was allowed to cool and diluted with ethyl acetate and water.The layers were separated and the ethyl acetate was dried over MgSO₄,filtered and concentrated. The material was purified on silica geleluting with 10% methanol/DCM (1% NH₄OH) to afford benzyl(S)-2-(cyanomethyl)-4-(7-(8-cyclopropylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(7 mg, 0.010 mmol, 25% yield).

Step B:2-((S)-4-(7-(8-Cyclopropylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:Benzyl(S)-2-(cyanomethyl)-4-(7-(8-cyclopropylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(9 mg, 0.01 mmol) was diluted with methanol (1 mL) followed by theaddition of Pd—C (1 mg, 0.01 mmol). The reaction was equipped with ahydrogen balloon and purged three times followed by stirring under anatmosphere of hydrogen for 4 hours. The solids were collected byfiltration, rinsed with methanol and the combined organic phase wasconcentrated to afford2-((S)-4-(7-(8-cyclopropylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(7 mg, 0.01 mmol, 97% yield).

Step C:2-((S)-4-(7-(8-Cyclopropylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile:2-((S)-4-(7-(8-cyclopropylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(10 mg, 0.019 mmol) was diluted with DMF (500 μL) followed by theaddition of DIEA (11 μl, 0.065 mmol), 2-fluoroacrylic acid (2.5 mg,0.028 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane2,4,6-trioxide (13 μl, 0.020 mmol). After stirring for 12 hours, thereaction was diluted with ethyl acetate and saturated sodiumbicarbonate. The layers were separated and the ethyl acetate was driedover MgSO₄, filtered and concentrated. The material was purified onsilica gel eluting with 10% methanol/DCM (1% NH₄OH) to afford2-((S)-4-(7-(8-cyclopropylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile(0.9 mg, 0.0015 mmol, 7.9% yield). ESI+APCI MS m/z 610.3 [M+H]⁺.

Example 591

2-((S)-1-(2-Fluoroacryloyl)-4-(7-(8-isopropylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Synthesized in the same fashion as Example 590 substituting isopropylzinc bromide for cyclopropyl zinc bromide in step A. ESI+APCI MS m/z612.3 [M+H]⁺.

Example 592

2-((S)-1-(2-Fluoroacryloyl)-4-(7-(1-methylisoquinolin-8-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Synthesized in the same fashion as Example 588 substituting8-bromo-1-methylisoquinoline for 1,8-dibromonaphthalene in step A.ESI+APCI MS m/z 585.3 [M+H]⁺.

Example 593

2-((S)-4-(7-(5-Chloroisoquinolin-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

Synthesized in the same fashion as Example 588 substituting4-bromo-5-chloroisoquinoline for 1,8-dibromonaphthalene in step A.ESI+APCI MS m/z 605.2 [M+H]⁺.

Example 594

2-((S)-4-(7-(8-Bromoisoquinolin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

Synthesized in the same fashion as Example 588 substituting8-bromo-1-chloroisoquinoline for 1,8-dibromonaphthalene in step A.ESI+APCI MS m/z 651.2 [M+H]⁺.

Example 595

2-((S)-4-(7-(1-chloroisoquinolin-8-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

Synthesized in the same fashion as Example 589 substituting8-bromo-1-chloroisoquinoline for 1,8-dibromonaphthalene in step A.ESI+APCI MS m/z 605.3 [M+H]⁺.

Example 596

2-((S)-4-(2-(((S)-1-Benzylpyrrolidin-2-yl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

Step A: Benzyl(S)-4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:Tert-butyl(S)-4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(3 g, 5.7 mmol) was dissolved in DCM (57 ml, 5.7 mmol) and treated withhydrochloric acid solution (4.0M in 1,4-dioxane) (7.1 ml, 28 mmol). Thereaction was stirred at room temperature for 1 hour. The reaction waswashed with 1M NaOH. The aqueous phase was extracted with additional DCM(2×), the combined organic phase was dried over MgSO₄ and concentratedin vacuo to give benzyl(S)-4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(2.4 g, 5.6 mmol, 99% yield). ESI+APCI MS m/z 427.2 [M+H]⁺.

Step B: Benzyl(S)-4-(2-chloro-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:Tris(dibenzylideneacetone)dipalladium(0) (1.030 g, 1.124 mmol) and9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (1.301 g, 2.249 mmol)were dissolved in 1,4-dioxane (56.22 ml, 5.622 mmol) and purged underargon for 5 minutes. The reaction was stirred at 100° C. under argon for15 minutes and the reaction cooled to room temperature. To the reactionwas added benzyl(S)-4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(2.4 g, 5.622 mmol), 1-bromo-8-methylnaphthalene (3.729 g, 16.87 mmol),and cesium carbonate (5.495 g, 16.87 mmol) under argon. The reaction wascapped under argon and stirred at 100° C. over night. The reaction wascooled to room temperature and the solids were removed by filtration.The filtrate was concentrated in vacuo and purified by normal phasechromatography (2×) on the CombiFlash using 0475% Hexanes/EtOAc as theeluent to give benzyl(S)-4-(2-chloro-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(2.532 g, 4.465 mmol, 79.42% yield). ESI+APCI MS m/z 567.2 [M+H]⁺.

Step C:2-((S)-4-(2-(((S)-1-Benzylpyrrolidin-2-ylmethoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:In a microwave tube a solution of benzyl(S)-4-(2-chloro-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(250 mg, 0.441 mmol) in dioxane (2204 μl, 0.441 mmol) was sparged withargon for 5 minutes (S)-(−)-1-benzyl-2-pyrrolidinemethanol (169 mg,0.882 mmol), Cs₂CO₃ (431 mg, 1.32 mmol),methanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II)(37.5 mg, 0.0441 mmol) were sequentially added under argon and thereaction sparged with Ar for an additional 5 minutes. The reactionmixture was capped and heated at 100° C. for 2 hours. The reaction wascooled to room temperature and ethyl acetate was added. The solids wereremoved by filtration, and the filtrate was concentrated and purified byflash chromatography eluting with 0→20% DCM/MeOH+2% NH₄OH. All fractionscontaining desired product were combined and concentrated to give2-((S)-4-(2-(((S)-1-benzylpyrrolidin-2-yl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(120 mg, 0.204 mmol, 77.2% yield). ESI+APCI MS m/z 722.4 [M+1]⁺.

Step D:2-((S)-4-(2-(((S)-1-benzylpyrrolidin-2-yl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:A solution of benzyl(S)-4-(2-(((S)-1-benzylpyrrolidin-2-yl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(200 mg, 0.277 mmol) in EtOH (2770 μl, 0.277 mmol) and THF (2770 μl,0.277 mmol) was purged with N₂ for 5 minutes. To this solution was addedpalladium (73.7 mg, 0.0693 mmol) (Degussa Type, 10 wt %, 50%-2O), andwas immediately capped and purged with N₂ for an additional 5 minutes.The solution was then stirred under one atmosphere of H₂ for 1 hour. Themixture was diluted with MeOH and filtered through packed celite. Thefiltrate was then concentrated in vacuo to provide crude2-((S)-4-(2-(((S)-1-benzylpyrrolidin-2-yl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(160 mg, 0.272 mmol, 98.3% yield). ESI+APCI MS m/z 588.4 [M+H]⁺.

Step E:2-((S)-4-(2-(((S)-1-Benzylpyrrolidin-2-yl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile:To a 25 mL RBF containing dichloromethane (2722 μl, 0.272 mmol) at 0° C.was added2-((S)-4-(2-(((S)-1-benzylpyrrolidin-2-yl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(160 mg, 0.272 mmol) and Hunig's base (95.1 μl, 0.544 mmol). Thereaction mixture was vigorously stirred while 2-fluoroacrylic acid (98.1mg, 1.09 mmol) was added in one portion. Next, 1-propanephosphonic acidcyclic anhydride (243 μl, 0.408 mmol) was added slowly to the stirringmixture. The reaction was stirred for 2 hours at 0° C. The reaction wastreated with basic water and the aqueous layer extracted with DCM (3×).The combined organic phase was concentrated in vacuo and the residueresuspended in a 60.40 mixture of MeCN:H₂O and purified (prep HPLC),eluting with 5→95%; MeCN/0.1% TFA in water/0.1% TFA to give product.Pure fractions were pooled and diluted with EtOAc and 1N NaOH and thelayers separated. The combined organic phase was washed with brine,dried over MgSO₄ and concentrated in vacuo to give2-((S)-4-(2-(((S)-1-benzylpyrrolidin-2-yl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile(8 mg, 0.0121 mmol, 4.45% yield). ESI+APCI MS m/z 660.4 [M+H]⁺.

Example 597

2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((S)-1-(2-fluoroethyl)pyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

Step A: Benzyl(S)-4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl-2-(cyanomethyl)piperazine-1-carboxylate:tert-butyl(S)-4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(2 g, 3.795 mmol) was dissolved in DCM (37.95 ml, 3.795 mmol) andtreated with hydrochloric acid solution (4.0 M in 1,4-dioxane) (4.744ml, 18.97 mmol). The reaction was stirred at room temperature for 1hour. The reaction was washed with 1M NaOH and the aqueous layerextracted with DCM (2×). The organic phase was combined, dried overNa₂SO₄ and concentrated to give benzyl(S)-4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(1.619 g, 3.792 mmol, 99.93% yield). ESI+APCI MS m/z 427.2 [M+H]⁺.

Step B: Benzyl(S)-4-(2-chloro-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:Tris(dibenzylideneacetone)dipalladium(0) (0.6946 g, 0.7585 mmol) and9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.8778 g, 1.517 mmol)were dissolved in 1,4-dioxane (37.92 ml, 3.792 mmol), purged under argonfor 5 minutes and stirred at 100° C. under argon for 15 minutes and thereaction cooled to room temperature. To the mixture was added benzyl(S)-4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(1.619 g, 3.792 mmol), 1-bromo-8-methylnaphthalene (2.515 g, 11.38mmol), and cesium carbonate (3.707 g, 11.38 mmol) under argon. Thereaction was capped under argon and stirred at 100° C. over night. Thereaction was cooled to room temperature and the solids removed byfiltration. The filtrate was concentrated in vacuo and purified bynormal phase chromatography (2×) using 0475% hexanes/EtOAc as the eluentto give benzyl(S)-4-(2-chloro-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(958 mg, 1.689 mmol, 44.54% yield). ESI+APCI MS m/z 567.2 [M+H]⁺.

Step C: tert-Butyl(S)-2-(((4-((S)-3-(cyanomethyl)piperazin-1-yl)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)pyrrolidine-1-carboxylate:In a microwave tube, a solution of benzyl(S)-4-(2-chloro-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(250 mg, 0.441 mmol) in dioxane (2204 μl, 0.441 mmol) was sparged withargon for 5 minutes(S)-(−)-1-(tert-Butoxycarbonyl)-2-pyrrolidinemethanol (222 mg, 1.10mmol), Cs₂CO₃ (431 mg, 1.32 mmol) andmethanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II)(37.5 mg, 0.0441 mmol) were sequentially added under argon and thereaction sparged with Ar for an additional 5 minutes. The reactionmixture was capped and heated at 100° C. for 2 hours. The reaction wascooled to room temperature and ethyl acetate was added. The solids wereremoved by filtration, the filtrate was concentrated and purified byflash chromatography eluting with 0→20% DCM/MeOH+2% NH₄OH. All fractionscontaining desired product were combined and concentrated to give benzyl(S)-4-(2-(((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(306 mg, 0.418 mmol, 94.8% yield). ESI+APCI MS m/z 598.3 [M+H]+.

Step D: Benzyl(S)-4-(2-(((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:tert-Butyl(S)-2-(((4-((S)-3-(cyanomethyl)piperazin-1-yl)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)pyrrolidine-1-carboxylate(93 mg, 0.1556 mmol) was dissolved in dichloromethane (1556 μl, 0.1556mmol) and treated with Hunig's base (135.9 μl, 0.7779 mmol) and benzylcarbonochloridate (33.31 μl, 0.2334 mmol). The reaction was stirred atroom temperature for 2 hours. The reaction was partitioned between DCMand water and the layers separated. The aqueous layer was extracted withDCM (2×). The combined organic phase was dried over Na₂SO₄, concentratedin vacuo and the residue purified by chromatography using 0→15%DCM/MeOH+2% NH₄OH as eluent. All fractions containing product werecombined and concentrated to give benzyl(S)-4-(2-(((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(367 mg, 0.5014 mmol, 322.3% yield). ESI+APCI MS m/z 732.4 [M+H]⁺.

Step E: Benzyl(S)-2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-pyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:Benzyl(S)-4-(2-(((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(367 mg, 0.501 mmol) was dissolved in DCM (5014 μl, 0.501 mmol) andtreated with TFA (193 μl, 2.51 mmol) and the reaction stirred at roomtemperature for 1 hour. No reaction was observed. The mixture wasconcentrated in vacuo and resuspended in DCM. To this was added HCl (4Min Dioxane, 500 μL) and the reaction stirred at room temperature for 1hour. The reaction was concentrated in vacuo and the residue partitionedbetween 1M NaOH and DCM. The combined organic phase was concentrated invacuo to give crude benzyl(S)-2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-pyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(192 mg, 0.304 mmol, 60.6% yield). ESI+APCI MS m/z 632.3 [M+H]⁺.

Step F: Benzyl(S)-4-(2-(((S)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)pyrrolidin-2-yl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:To a stirred solution of benzyl(S)-2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-pyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(150 mg, 0.23742 mmol) in 2.5 mL of DMF was added sodium hydride (60%dispersion in mineral oil (8.5465 mg, 0.35614 mmol)). After 15 minutes(2-bromoethoxy)(tert-butyl)dimethylsilane (142.00 mg, 0.59356 mmol) wasadded and the reaction heated to 75° C. for 3.5 hours. The reaction wascooled to room temperature and partitioned between water and EtOAc andthe layers separated. The aqueous layer was extracted with EtOAc and thecombined organic phase washed with more water and brine, dried overNa₂SO₄ and concentrated in vacuo to give crude benzyl(S)-4-(2-(((S)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)pyrrolidin-2-yl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(187 mg, 0.237 mmol, 99.7% yield). ESI+APCI MS m/z 790.4 [M+H]⁺.

Step G:2-((S)-4-(2-(((S)-1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)pyrrolidin-2-yl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:A solution of benzyl(S)-4-(2-(((S)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)pyrrolidin-2-yl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(187 mg, 0.237 mmol) in EtOH (2367 μl, 0.237 mmol) and THF (2367 μl,0.237 mmol) was purged with N₂ for 5 minutes. To this solution was addedpalladium (63.0 mg, 0.0592 mmol) (Degussa Type, 10 wt %, 50% H₂O), andwas immediately capped and purged with N₂ for an additional 5 minutes.The solution was then stirred under one atmosphere of H₂ overnight. Themixture was diluted with MeOH and filtered through packed celite. Thefiltrate was then concentrated in vacuo to provide crude2-((S)-4-(2-(((S)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)pyrrolidin-2-yl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(134 mg, 0.204 mmol, 86.3% yield). ESI+APCI MS m/z 656.4 [M+H]⁺.

Step H:2-((S)-4-(2-(((S)-1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)pyrrolidin-2-yl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile:At 0° C., to a 25 mL RBF containing N,N-dimethylformamide (2043 μl,0.204 mmol) was added2-((S)-4-(2-(((S)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)pyrrolidin-2-yl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(134 mg, 0.204 mmol) and Hunig's base (71.4 μl, 0.409 mmol). Thereaction mixture was vigorously stirred while 2-fluoroacrylic acid (22.1mg, 0.245 mmol) was added in one portion. Next, 1-propanephosphonic acidcyclic anhydride (182 μl, 0.306 mmol) was added slowly to the stirringmixture. The reaction was stirred for 1 hour at 0° C. The reaction wastreated with aqueous NaOH and the aqueous layer extracted with EtOAc(3×). The combined organic phase was concentrated in vacuo to give crude2-((S)-4-(2-(((S)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)pyrrolidin-2-yl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile(120 mg, 0.165 mmol, 80.7% yield). ESI+APCI MS m/z 728.4 [M+H]⁺.

Step I:2-((S)-1-(2-Fluoroacryloyl)-4-(2-(((S)-1-(2-hydroxyethyl)pyrrolidin-2-yl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:2-((S)-4-(2-(((S)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)pyrrolidin-2-yl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile(50 mg, 0.069 mmol) was dissolved in dichloromethane (687 μl, 0.069mmol) and treated with hydrogen chloride (52 μl, 0.21 mmol) (4M indioxane). The reaction stirred at room temperature for 1 hour. Thereaction was then concentrated in vacuo and resuspended in a 60:40mixture of MeCN:H₂O and purified (prep HPLC) eluting with 5495%MeCN/0.1% TFA in water/0.1% TFA. Fractions containing product werecombined and partitioned between 1 M NaOH and DCM and the layersseparated and the aqueous layer extracted with additional DCM. Thecombined organic phase was dried over Na₂SO₄ and concentrated in vacuoto give2-((S)-1-(2-fluoroacryloyl)-4-(2-(((S)-1-(2-hydroxyethyl)pyrrolidin-2-yl)methoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(2.7 mg, 0.0044 mmol, 6.4% yield). ESI+APCI MS m/z 614.3 [M+H]⁺.

Example 598

2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((S)-1-(2-fluoroethyl)pyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

Step A:2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((S)-1-(2-fluoroethyl)pyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile:2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-pyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile(30 mg, 0.0508 mmol) was dissolved in acetonitrile (508 μl, 0.0508 mmol)and cesium carbonate (19.9 mg, 0.0610 mmol) was added in one portion. Tothis mixture was then added 1-fluoro-2-iodoethane (3.72 μl, 0.0458 mmol)and the reaction stirred at 60° C. over night. The reaction was cooledto room temperature, the solids were removed by filtration, and thefiltrate was concentrated in vacuo. The residue was resuspended in 60:40MeCN:water and purified (prep HPLC), eluting with 5495% MeCN/0.1% TFA inwater/0.1% TFA. Fractions containing desired product were combined andpartitioned between EtOAc and 1M NaOH and the layers separated. Theaqueous layer was extracted with additional EtOAc (2×). The combinedorganic phase was dried over Na₂SO₄ and concentrated in vacuo to give2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-(2-fluoroethyl)pyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile(4.8 mg, 0.00755 mmol, 14.8% yield). ESI+APCI MS m/z 636.3 [M+H]⁺.

Example 599

2-((S)-1-(2-Fluoroacryloyl)-4-(7-(8-methylnaphthalen-1-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methyl)thio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: tert-Butyl(S)-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate: To asolution of tert-butyl (S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate(3.0 g, 14.91 mmol) in DCM (74.53 ml, 14.91 mmol) cooled to 0° C. wasadded N-ethyl-N-isopropylpropan-2-amine (4.01 ml, 22.36 mmol) followedby addition of methanesulfonyl chloride (1.38 ml, 17.89 mmol) over thecourse of 1 minute and the reaction stirred at 0° C. for 1 hr. Thereaction was next washed with 1:1 water/brine (10 mL) and the layersseparated. The combined organic phase was next dried over MgSO₄,filtered and concentrated in vacuo. The material was next purified bychromatography using 0-10% MeOH in DCM as eluent to give tert-butyl(S)-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (3.786 g,13.55 mmol, 90.9% yield).

Step B: tert-Butyl(S)-2-(((3-methoxy-3-oxopropyl)thio)methyl)pyrrolidine-1-carboxylate:tera-Butyl (S)-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate(2.00 g, 7.16 mmol) and Cs₂CO₃ (4.665 g, 14.32 mmol) were placed indioxane (10 mL) and stirred for 3 hours at room temperature. NaOH (0.5M)was added and the mixture was extracted with DCM. The combined organicphase was concentrated and the residue purified by silica gel (0-12%MeOH in DCM with 0.25% NH4OH) to provide tert-butyl(S)-2-(((3-methoxy-3-oxopropyl)thio)methyl)pyrrolidine-1-carboxylate(2.172 g, 7.16 mmol, 99% yield).

Step C: Methyl (S)-3-(((1-methylpyrrolidin-2-yl)methyl)thio)propanoate:To a vial was added tert-butyl(S)-2-(((3-methoxy-3-oxopropyl)thio)methyl)pyrrolidine-1-carboxylate(2.172 g, 7.16 mmol) in formic acid (6.751 ml, 179.0 mmol) followed byaddition of formaldehyde (10.76 ml, 143.2 mmol)(37% aqueous). Themixture was then heated to 65° C. and stirred for 18 hours. The reactionwas cooled and saturated bicarbonate was added slowly and the mixturewas extracted with 10% MeOH in DCM (3×20 mL). The extracts werecombined, dried over MgSO₄ and concentrated. The residue was purified bysilica gel (5-20% MeOH in DCM with 0.25% NH4OH) to provide methyl(S)-3-(((1-methylpyrrolidin-2-yl)methyl)thio)propanoate (186 mg, 0.86mmol, 12% yield).

Step D: tert-Butyl4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methyl)thio)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:Methyl (S)-3-(((1-methylpyrrolidin-2-yl)methyl)thio)propanoate (186 mg,0.854 mmol) was placed in dioxane (5 mL). KOtBu (1708 μl, 1.71 mmol) wasadded and the mixture was stirred for 30 minutes. tert-Butyl(S)-4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(300 mg, 0.569 mmol) was added and the mixture was heated to 80° C. for24 hours. The mixture was cooled, diluted with water and extracted withDCM (3×15 mL). The extracts were combined and concentrated. The residuewas purified by silica gel (0-15% MeOH in DCM with 0.25% NH₄OH) toprovide tert-butyl4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methyl)thio)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(72 mg, 0.116 mmol, 20.3% yield).

Step E: Benzyl(S)-2-(cyanomethyl)-4-(2-((((S)-1-methylpyrrolidin-2-yl)methyl)thio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:tert-Butyl4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methyl)thio)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(72 mg, 0.12 mmol) was placed in DCM (5 mL) and cooled to 0° C. HCl (145μl, 0.58 mmol) was added and the reaction warmed to room temperature andstirred for 18 hours. The reaction was concentrated and was brought upin DCM. Saturated bicarbonate was added and the mixture was extractedwith DCM (3×20 mL). The organic layers were combined, dried over MgSO₄and concentrated to provide benzyl(S)-2-(cyanomethyl)-4-(2-((((S)-1-methylpyrrolidin-2-yl)methyl)thio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(61 mg, 0.12 mmol).

Step F: Benzyl(S)-2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methyl)thio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:To a solution of benzyl(S)-2-(cyanomethyl)-4-(2-((((S)-1-methylpyrrolidin-2-yl)methyl)thio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(61 mg, 0.12 mmol) in toluene (2 mL) was added1-bromo-8-methylnaphthalene (78 mg, 0.35 mmol) and the reaction degassedwith argon for 15 minutes followed by addition of Cs₂CO₃ (190 mg, 0.58mmol), Pd₂(dba)₃ (21 mg, 0.023 mmol) and Xantphos (27 mg, 0.047 mmol)and the reaction heated to 100° C. for 18 hr. The solids were removed byfiltration, and the filtrate was concentrated in vacuo. The residue wasnext purified by chromatography using 1→12% MeOH/DCM with 2% NH₄OH asadditive to give benzyl(S)-2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methyl)thio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(54 mg, 0.082 mmol, 70% yield).

Step G:2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methyl)thio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:Benzyl(S)-2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methyl)thio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(54 mg, 0.082 mmol) was placed in DCM (10 mL) and the reaction cooled to0° C. AcOH (14.01 μl, 0.244 mmol) and TMS-I (69.67 μl, 0.490 mmol) wereadded and the reaction slowly warmed to room temperature and stirred for1 hour. Saturated bicarbonate was added and the mixture was extractedwith DCM. The extracts were concentrated and the residue purified byreverse phase chromatography (5-95% MeCN in water with 0.1% TFA). Theisolated product was then free based by bring up in DCM and addingsaturated bicarbonate. The organic layer was separated, dried over MgSO₄and concentrated to provide2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methyl)thio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(8 mg, 0.15 mmol, 19%).

Step H:2-((S)-1-(2-Fluoroacryloyl)-4-(7-(8-methylnaphthalen-1-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methyl)thio-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:To a 0° C. solution of N,N-dimethylformamide (152 μl, 0.015 mmol) wasadded2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methyl)thio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(8.0 mg, 0.015 mmol) and triethylamine (7.37 μl, 0.053 mmol). Thereaction mixture was vigorously stirred while 2-fluoroacrylic acid (4.10mg, 0.046 mmol) was added in one portion. Next, 1-propanephosphonic acidcyclic anhydride (13.5 μl, 0.023 mmol) was added slowly to the stirringmixture. The reaction was stirred at room temperature for 20 minutes.Water was added and the mixture was extracted with DCM and the extractswere concentrated. The residue was purified by silica gel (0-12% MeOH inDCM with 0.25% NH₄OH) to provide2-((S)-1-(2-fluoroacryloyl)-4-(7-(8-methylnaphthalen-1-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methyl)thio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(2.3 mg, 0.0038 mmol, 25.3 yield). ES+APCI MS m/z 600.3 [M+H]⁺.

Example 600

2-((S)-4-(7-(5-Chloro-4-(trifluoromethyl)pyridin-3-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

2-((S)-4-(7-(5-Chloro-4-(trifluoromethyl)pyridin-3-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile,was prepared according to Example 359 substituting3,5-dichloro-4-(trifluoromethyl)pyridine for 1-promo-8-methylnaphthalenein step A. ES+APCI MS m/z 623.2 [M+H]⁺.

2-[(2S)-4-[2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-fluorobut-2-enoyl]piperazin-2-yl]acetonitrile

Step A: Benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 841 μmol, 1 eq) and[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methanol (191 mg, 1.26 mmol,1.5 eq) in toluene (10 mL) was added t-BuONa (162 mg, 1.68 mmol, 2 eq).The mixture was stirred at 0° C. for 30 minutes. Upon completion, themixture was diluted with water (10 mL) and extracted with EtOAc (2×40mL). The organic layers were dried over Na₂SO₄ and concentrated undervacuum. The residue was purified by reversed phase flash [water (0.1%FA)/acetonitrile]. The desired fractions were collected and neutralizedwith NaHCO₃, concentrated under vacuum to remove MeCN and extracted withEtOAc (2×100 mL). The organic layers were dried over Na₂SO₄ andconcentrated under vacuum to give benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(300 mg, 418 μmol, 50% yield, 95% purity) as a yellow solid. LCMS [ESI,M+1]: 682.

Step B:2-[(2S)-4-[2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(260 mg, 381 μmol, 1 eq) in MeOH (4 mL) was added Pd/C (120 mg, 10%purity), NH₃/MeOH (3 mL, 20% purity) under N₂. The suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred under H₂ (15 psi) at 15° C. for 1 hour. Upon completion, themixture was filtered and the filtrate was concentrated under vacuum togive2-[(2S)-4-[2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(180 mg, 296 μmol, 78% yield, 90% purity) as a yellow solid useddirectly into the next step without further purification. LCMS [ESI,M+1]: 548.

Step C: 2-[(2S)-4-[2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-fluorobut-2-enoyl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(150 mg, 274 umol, 1 eq), TEA (222 mg, 2.19 mmol, 305 uL, 8 eq) and(E)-4-fluorobut-2-enoic acid (57.0 mg, 548 μmol, 2 eq) in EA (3 mL) wasadded T3P (523 mg, 822 μmol, 489 μL, 50% purity in EA, 3 eq) at −70° C.The mixture was stirred at −70° C. for 1 hour. Upon completion, thereaction mixture was quenched with 1 M HCl (2.2 mL) at −70° C., stirreduntil no ice remained. Layers were separated. The organic layer wasbasified with saturated NaHCO₃ aqueous solution to pH=8 and extractedwith ethyl acetate (15 mL×3). The combined organic layers were driedover Na₂SO₄, filtered and concentrated under vacuum. The residue waspurified by chromatography (Al₂O₃, EtOAc/MeOH 1/0 to 20/1) followed byprep-HPLC (column: Waters Xbridge 150*25 5 u; mobile phase: [water(0.05% ammonia hydroxide v/v)-ACN]; B %: 55%-85%, 10 min). The desiredfractions were collected and lyophilized to give2-[(2S)-4-[2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-fluorobut-2-enoyl]piperazin-2-yl]acetonitrile(50.6 mg, 78 μmol, 29% yield, 98% purity) as a white solid. LCMS [ESI,M+1]: 634.

¹H NMR (400 MHz, chloroform-d) δ=7.70 (br d, J=8.0 Hz, 1H), 7.66 (t,J=8.0 Hz, 1H), 7.45-7.38 (m, 1H), 7.38-7.32 (m, 1H), 7.27-7.18 (m, 2H),7.09-6.93 (m, 1H), 6.60 (br d, J=14.8 Hz, 1H), 5.32-4.93 (m, 3H), 4.64(br s, 1H), 4.45 (td, J=5.2, 11.2 Hz, 1H), 4.32-3.63 (m, 6H), 3.58-3.36(m, 3H), 3.25-2.96 (m, 5H), 2.93 (s, 3H), 2.88-2.77 (m, 1H), 2.75-2.50(m, 3H), 2.46 (d, J=4.4 Hz, 3H), 2.34-2.15 (m, 1H).

Example 602

2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

Step A: benzyl(2S)-2-cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxyl]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a mixture of benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(300 mg, 593 umol, 1.0 eq), 1-bromonaphthalene (184 mg, 890 μmol, 124μL, 1.5 eq), Pd₂(dba)₃ (54.3 mg, 59.3 μmol, 0.1 eq), Cs₂CO₃ (483 mg,1.48 mmol, 2.5 eq) and RuPhos (55.4 mg, 119 umol, 0.2 eq) in toluene (10mL) was degassed and purged with N₂ for 3 times, and then the mixturewas stirred at 90° C. for 3 hours under N₂ atmosphere. Upon completion,the mixture was diluted with water (10 mL) and extracted with ethylacetate (1×50 mL) and the organic layer was separated, dried over sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by reverse phase HPLC (0.1% FA condition). The residue wasbasified with saturated aqueous NaHCO₃ solution to pH˜8, and thenextracted with ethyl acetate (2×25 mL). The organic phase was separated,dried over sodium sulfate, filtered and concentrated under vacuum.Benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 317 μmol, 53% yield, 100% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 632.

Step B:2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(100 mg, 158 μmol, 1.0 eq) in MeOH (10 mL) was added Pd/C (20 mg, 10%purity) and NH₃·MeOH (8 mL, 20% purity) under N₂. The suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred under H₂ (15 psi) at 25° C. for 1 hour. Upon completion, themixture was concentrated under vacuum.2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(70 mg, crude) was obtained as a yellow oil and used into next stepswithout further purification. LCMS [ESI, M+1]: 498.

Step C:2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(60 mg, 121 umol, 1.0 eq), 2-fluoroprop-2-enoic acid (21.7 mg, 241 μmol,2.0 eq) and Et₃N (97.6 mg, 965 umol, 134 uL, 8.0 eq) in ethyl acetate (6mL) was added T3P (230 mg, 362 μmol, 215 μL, 50% purity, 3.0 eq) at 0°C. The mixture was stirred at 0-25° C. for 1 hour. Upon completion, themixture was diluted with water (6 mL). The organic layer was separated,washed with brine (1×10 mL), dried over sodium sulfate, filtered andconcentrated under vacuum. The mixture was purified by columnchromatography (SiO₂, ethyl acetate/methanol=20/1 to 5/1). The residuewas purified by prep-HPLC (column: Waters Xbridge 150*25 5 u, mobilephase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 60%-78%, 10 min).The residue was concentrated under reduced pressure to remove ACN, andthen lyophilized.2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(7.23 mg, 12.7 μmol, 11% yield, 100% purity) was obtained as a whitesolid. LCMS [ESI, M+1]: 571.

1H NMR (400 MHz, chloroform-d) δ=8.27-8.16 (m, 1H), 7.91-7.81 (m, 1H),7.61 (d, J=8.4 Hz, 1H), 7.55-7.47 (m, 2H), 7.43 (t, J=7.6 Hz, 1H), 7.15(d, J=7.2 Hz, 1H), 5.56-5.33 (m, 1H), 5.26 (dd, J=3.2, 16.8 Hz, 1H),4.85 (br s, 1H), 4.41 (dd, J=5.2, 10.8 Hz, 1H), 4.34-4.24 (m, 2H),4.22-3.96 (m, 4H), 3.75-3.21 (m, 4H), 3.12 (br t, J=6.8 Hz, 2H),3.04-2.92 (m, 2H), 2.87 (m, 2H), 2.70 (m, 1H), 2.50 (s, 3H), 2.38-2.23(m, 1H), 2.15-1.99 (m, 1H), 1.94-1.73 (m, 3H).

Example 603

2-[(2S)-4-[2-(cyclopentylmethoxy)-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile

Step A: benzyl(2S)-2-(cyanomethyl)-4-[2-(cyclopentylmethoxy)-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of cyclopentylmethanol (50.5 mg, 504 μmol, 54.6 μL, 3.0eq) and benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(100 mg, 168 μmol, 1.0 eq) in toluene (5 mL) was added t-BuONa (48.5 mg,504 umol, 3.0 eq) at −10° C. The mixture was stirred at −10° C. for 0.5hour. Upon completion, the reaction mixture was quenched with water (5mL) at −10° C., and then extracted with ethyl acetate (2×20 mL). Thecombined organic layers were washed with brine (1×20 mL), dried overNa₂SO₄, filtered and concentrated under vacuum. The residue was purifiedby column chromatography (SiO₂, petroleum ether/ethyl acetate=50/1 to3/1). The compound benzyl(2S)-2-(cyanomethyl)-4-[2-(cyclopentylmethoxy)-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(58 mg, 91.6 μmol, 54% yield, 99.6% purity) was obtained as a whitesolid. LCMS [ESI, M+1]: 631.

¹H NMR (400 MHz, chloroform-d) δ=7.72-7.61 (m, 2H), 7.46-7.30 (m, 7H),7.26-7.16 (m, 2H), 5.27-5.15 (m, 2H), 4.69 (br s, 1H), 4.32-3.72 (m,7H), 3.59-3.30 (m, 2H), 3.24-2.87 (m, 7H), 2.87-2.30 (m, 4H), 1.90-1.76(m, 2H), 1.64 (m, 2H), 1.57-1.51 (m, 1H), 1.42-1.21 (m, 3H).

Step B:2-[(2S)-4-[2-(cyclopentylmethoxy)-7-(8-methyl-1-naphthyl-6,8-dihydro-5H-pyrido[3,4d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[2-(cyclopentylmethoxy)-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(58 mg, 92.0 μmol, 1.0 eq) in MeOH (3 mL) was added Pd/C (20 mg, 10%purity) and NH₃·MeOH (2 mL, 20% purity) under N₂. The suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred under H₂ (15 psi) at 25° C. for 1 hour. Upon completion, themixture was concentrated under vacuum.2-[(2S)-4-[2-(cyclopentylmethoxy)-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(34 mg, crude) was obtained as a yellow oil and used into next stepswithout further purification. LCMS [ESI, M+1]: 497.

Step C:2-[(2S)-4-[2-(cyclopentylmethoxy)-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[2-(cyclopentylmethoxy)-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(30 mg, 60.4 μmol, 1.0 eq), 2-fluoroprop-2-enoic acid (16.3 mg, 181umol, 3.0 eq) and Et₃N (55.0 mg, 544 μmol, 75.7 μL, 9.0 eq) in EA (2.0mL) was added T3P (154 mg, 242 umol, 144 uL, 50% purity, 4.0 eq) at 0°C. The mixture was stirred at 25° C. for 1 hour. Upon completion, themixture was diluted with water (6 mL). The organic layer was separated,washed with brine (1×10 mL), dried over sodium sulfate, filtered andconcentrated under vacuum. The mixture was purified by columnchromatography (SiO₂, petroleum ether/ethyl acetate=20/1 to 1/1). Theresidue was purified by prep-HPLC (column: Waters Xbridge 150*25 5 u;mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 65%-95%,10 min). The residue was concentrated under reduced pressure to removeACN, and then lyophilized.2-[(2S)-4-[2-(cyclopentylmethoxy)-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile(8.85 mg, 15.3 μmol, two steps 17% yield, 98.2% purity) was obtained asa yellow solid. LCMS [ESI, M+1]: 569.

¹H NMR (400 MHz, chloroform-d) δ=7.70 (br d, J=8.0 Hz, 1H), 7.67-7.61(m, 1H), 7.46-7.36 (m, 1H), 7.36-7.31 (m, 1H), 7.27-7.17 (m, 2H),5.56-5.32 (m, 1H), 5.25 (dd, J=3.6, 16.8 Hz, 1H), 4.89 (br s, 1H),4.33-3.98 (m, 5H), 3.95-3.72 (m, 2H), 3.60-3.39 (m, 2H), 3.30-2.96 (m,4H), 2.92 (s, 3H), 2.91-2.73 (m, 2H), 2.69-2.54 (m, 1H), 2.45-2.29 (m,1H), 1.93-1.74 (m, 2H), 1.69-1.62 (m, 2H), 1.60-1.53 (m, 2H), 1.45-1.25(m, 2H).

Example 604

2-[(2S)-4-[7-(5,6-dimethyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile

Step A: benzyl(2S)-2-(cyanomethyl)-4-[7-5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.A mixture of benzyl (2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1 g, 1.98 mmol, 1 eq),4-bromo-5,6-dimethyl-1-tetrahydropyran-2-yl-indazole (795 mg, 2.57 mmol,1.3 eq), RuPhos (369 mg, 791 umol, 0.4 eq), Cs₂CO₃ (1.61 g, 4.94 mmol,2.5 eq) and Pd₂(dba)₃ (362 mg, 396 umol, 0.2 eq) in toluene (20 mL) wasde-gassed and then heated to 90° C. for 8 hours under N₂. Uponcompletion, the mixture was filtered and the filtrate was concentratedunder vacuum. The residue was purified by reverse phase flash [water(0.1% FA)/acetonitrile]. The desired fractions were collected andneutralized with solid NaHCO₃, concentrated under vacuum to remove MeCNand extracted with EtOAc (2×40 mL). The organic layers were dried overNa₂SO₄ and concentrated under vacuum to give benzyl(2S)-2-(cyanomethyl)-4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(900 mg, 1.23 mmol, 62% yield, 100% purity) as a brown solid.

¹H NMR (400 MHz, chloroform-d) δ=7.98 (s, 1H), 7.43-7.33 (m, 5H), 7.22(s, 1H), 5.66 (dd, J=2.8, 9.6 Hz, 1H), 5.20 (s, 2H), 4.68 (br s, 1H),4.39 (dd, J=4.8, 10.0 Hz, 1H), 4.25 (s, 2H), 4.18-4.14 (m, 1H), 4.04 (brd, J=12.0 Hz, 2H), 3.95-3.84 (m, 1H), 3.75 (dt, J=2.8, 10.8 Hz, 1H),3.50 (br t, J=5.2 Hz, 2H), 3.30 (br s, 2H), 3.13-2.98 (m, 2H), 2.95-2.52(m, 6H), 2.47 (s, 3H), 2.43 (s, 3H), 2.32 (s, 3H), 2.30-2.23 (m, 1H),2.22-2.11 (m, 1H), 2.07 (br d, J=3.2 Hz, 1H), 1.89-1.63 (m, 8H).

Step B:2-[(2S)-4-[7-5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.9 g, 1.23 mmol, 1 eq) in MeOH (20 mL) was added NH₃·MeOH (20 mL, 20%purity), Pd/C (0.45 g, 10% purity) under N₂. The suspension was degassedunder vacuum and purged with H₂ several times. The mixture was stirredunder H₂ (15 psi) at 25° C. for 1 hour. Upon completion, the catalystwas removed by filtering through a plug of celite. The solvent wasremoved under reduced pressure.2-[(2S)-4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(620 mg, 1.03 mmol, 84% yield, 100% purity) was obtained as a yellowsolid which was used directly in the next step without furtherpurification. LCMS [ESI, M+1]: 600.

Step C:2-[(2S)-4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(600 mg, 1.00 mmol, 1 eq) in DMF (8 mL) was added 2-fluoroprop-2-enoicacid (180 mg, 2.00 mmol, 2 eq) in EA (4 mL) and TEA (304 mg, 3.00 mmol,414 μL, 3 eq) followed by T3P (955 mg, 1.50 mmol, 892 μL, 50% purity inEtOAc, 1.5 eq) at 0° C. The mixture was stirred at 25° C. for 0.5 hour.Upon completion, the mixture was diluted with water (20 mL) andextracted with EtOAc (3×20 mL). The organic layers were dried overNa₂SO₄ and concentrated under vacuum. The residue was purified byreverse phase flash [water (0.1% FA)/acetonitrile]. The desiredfractions were collected and neutralized with solid NaHCO₃, concentratedunder vacuum to remove MeCN and extracted with EtOAc (3×100 mL). Theorganic layers were dried over Na₂SO₄ and concentrated under vacuum togive2-[(2S)-4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile(380 mg, 554 μmol, 55% yield, 98% purity) as a yellow solid. LCMS [ESI,M+1]: 672.

¹H NMR (400 MHz, chloroform-d) δ=7.98 (s, 1H), 7.22 (s, 1H), 5.66 (dd,J=2.4, 9.2 Hz, 1H), 5.51-5.32 (m, 1H), 5.25 (br dd, J=3.6, 16.8 Hz, 1H),5.09-4.59 (m, 1H), 4.44-4.33 (m, 1H), 4.26 (br s, 2H), 4.19-4.14 (m,1H), 4.05 (br d, J=14.4 Hz, 2H), 4.00-3.91 (m, 1H), 3.76 (dt, J=2.4,11.2 Hz, 1H), 3.59-3.39 (m, 3H), 3.37-3.21 (m, 1H), 3.14-3.02 (m, 2H),2.90-2.52 (m, 6H), 2.48 (s, 3H), 2.43 (s, 3H), 2.33 (s, 3H), 2.29-2.23(m, 1H), 2.22-2.08 (m, 2H), 1.90-1.69 (m, 8H).

Step D: 2-[(2S)-4-[7-(5,6-dimethyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile(360 mg, 536 μmol, 1 eq) in DCM (0.4 mL) was added TFA (1.22 g, 10.7mmol, 794 μL, 20 eq). The mixture was stirred at 25° C. for 2 hours.Upon completion, the mixture was diluted with DCM (10 mL) andneutralized with saturated NaHCO₃ solution. The separated aqueous layerwas extracted with DCM (2×10 mL). Combined organic layers were driedover Na₂SO₄ and concentrated under vacuum. The residue was purified byreverse phase flash [water (0.1% FA)/acetonitrile]. The desiredfractions were collected and neutralized with solid NaHCO₃, concentratedunder vacuum to remove MeCN and extracted with EtOAc (2×15 mL). Theorganic layers were dried over Na₂SO₄ and concentrated under vacuum. Theresidue was purified by prep-HPLC (column: Xtimate C18 150*25 mm*5 um;mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 40%-70%,10 min). The desired fractions were collected and lyophilized to give2-[(2S)-4-[7-(5,6-dimethyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile(73.3 mg, 120 μmol, 22% yield, 96.6% purity) as a white solid. LCMS[ESI, M+1]: 588.

¹H NMR (400 MHz, chloroform-d) δ=9.97 (br s, 1H), 8.04 (s, 1H), 7.15 (s,1H), 5.55-5.31 (m, 1H), 5.26 (dd, J=3.6, 16.8 Hz, 1H), 5.08-4.50 (m,1H), 4.39 (dd, J=4.8, 10.8 Hz, 1H), 4.29 (s, 2H), 4.20-3.68 (m, 4H),3.65-3.27 (m, 4H), 3.10 (br t, J=7.8 Hz, 2H), 3.02-2.72 (m, 4H),2.71-2.60 (m, 1H), 2.48 (s, 3H), 2.42 (s, 3H), 2.34 (s, 3H), 2.31-2.24(m, 1H), 2.12-2.01 (m, 1H), 1.93-1.73 (m, 3H).

Example 605

2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[7-(8-methyl-1-naphthyl)-2-(2-pyridylmethoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

Step A: benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-(2-pyridylmethoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of 2-pyridylmethanol (55.1 mg, 504 μmol, 48.7 μL, 3.0 e/q)and benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(100 mg, 168 μmol, 1.0 eq) in toluene (5.00 mL) was added t-BuONa (48.5mg, 504 μmol, 3.0 eq) at −10° C. The mixture was stirred at −10° C. for0.5 hour. Upon completion, the mixture was quenched with water (5.00 mL)and extracted with ethyl acetate (2×10 mL). The combined organic layerswere washed with brine (1×10 mL), dried over Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by columnchromatography (SiO₂, petroleum ether/ethyl acetate 50/1 to 1/1). Benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-(2-pyridylmethoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(64.0 mg, 98.8 μmol, 59% yield, 98.8% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 641.

Step B:2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-(2-pyridylmethoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-(2-pyridylmethoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(64.0 mg, 100 μmol, 1.0 eq) in MeOH (3.00 mL) was added Pd/C (20.0 mg,10% purity) and NH₃·MeOH (2.00 mL, 20% purity) under N₂. The suspensionwas degassed under vacuum and purged with H₂ several times. The mixturewas stirred under H₂ (15 psi) at 25° C. for 1 hour. Upon completion, themixture was concentrated under vacuum. The residue was purified bycolumn chromatography (SiO₂, dichloromethane/methanol=100/1 to 8/1).2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-(2-pyridylmethoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(15.0 mg, 19.3 μmol, 19% yield, 64.9% purity) was obtained as a yellowoil. LCMS [ESI, M+1]: 506.

Step C:2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[7-(8-methyl-1-naphthyl)-2-(2-pyridylmethoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-(2-pyridylmethoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(10.0 mg, 19.8 μmol, 1.0 eq), 2-fluoroprop-2-enoic acid (5.34 mg, 59.3μmol, 3.0 eq) and Et₃N (18.0 mg, 178 μmol, 24.8 μL, 9.0 eq) in EtOAc(2.00 mL) was added T3P (50.3 mg, 79.1 μmol, 47.1 μL, 50% purity inethyl acetate, 4.0 eq) at 0° C. The mixture was stirred at 25° C. for 1hour Upon completion, the mixture was diluted with water (3.00 mL). Theorganic layer was separated, washed with brine (1×10 mL), dried oversodium sulfate, filtered and concentrated under vacuum. The mixture waspurified by column chromatography (SiO₂, ethyl acetate/methanol=50/1 to10/1). The residue was purified by prep-HPLC (column. Xtimate C18 150*25mm*5 um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %:50%-80%, 10 min). The residue was concentrated under reduced pressure toremove ACN, and then lyophilized.2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[7-(8-methyl-1-naphthyl)-2-(2-pyridylmethoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(1.41 mg, 2.44 umol, 12% yield, 99.8% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 579.

¹H NMR (400 MHz, chloroform-d) δ=8.61-8.55 (m, 1H), 7.74-7.62 (m, 3H),7.55-7.48 (m, 1H), 7.45-7.32 (m, 2H), 7.26-7.17 (m, 3H), 5.52-5.48 (m,2H), 5.47-5.33 (m, 1H), 5.25 (dd, J=3.6, 17.2 Hz, 1H), 4.79 (br s, 1H),4.38-3.73 (m, 6H), 3.61-3.41 (m, 2H), 3.26-3.12 (m, 2H), 3.09-2.95 (m,2H), 2.92 (s, 3H), 2.85-2.56 (m, 2H).

Example 606

2-((S)-4-(7-(5,6-dimethyl-1H-indazol-4-yl)-2-(((2S,4R)4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

Step A: Benzyl(2S)-2-(cyanomethyl)-4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.A mixture of benzyl(2S)-2-(cyanomethyl-4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(5.0 g, 11.4 mmol, 1.0 eq),4-bromo-5,6-dimethyl-1-tetrahydropyran-2-yl-indazole (7.05 g, 22.8 mmol,2.0 eq) Pd₂(dba)₃ (2.09 g, 2.28 mmol, 0.2 eq), RuPhos (2.13 g, 4.56mmol, 0.4 eq) and Cs₂CO₃ (9.29 g, 28.5 mmol, 2.5 eq) in toluene (100 mL)was degassed and purged with N₂ 3 times, and then the mixture wasstirred at 90° C. for 8 hours under N₂ atmosphere. The reaction mixturewas diluted with water (100 mL) and extracted with ethyl acetate (3×200ml). The combined organic layers were washed with brine (100 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=20/1 to 2/1) and further purified byreverse phase flash [water (0.1% formic acid)/acetonitrile)]. Themixture was adjusted pH˜7 with saturated NaHCO₃ aqueous solution andextracted with ethyl acetate (3×100 mL). The combined organic layerswere washed with brine (50 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give the product. Benzyl(2S)-2-(cyanomethyl)-4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(4.90 g, 7.20 mmol, 63% yield, 98% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 667.

¹H NMR (400 MHz, chloroform-d) δ=7.98 (s, 1H), 7.50-7.31 (m, 5H), 7.22(s, 1H), 5.66 (dd, J=2.4, 9.6 Hz, 1H) 5.27-5.13 (m, 2H), 4.69 (br s,1H), 4.27 (s, 2H), 4.13-3.97 (m, 3H), 3.89 (d, J=11.6 Hz, 1H), 3.81-3.68(m, 1H), 3.51 (t, J=5.2 Hz, 2H), 3.30 (br s, 2H), 3.04 (t, J=11.6 Hz,1H), 2.93-2.66 (m, 4H), 2.62-2.48 (m, 4H), 2.43 (s, 3H), 2.32 (s, 3H),2.23-2.12 (m, 1H), 2.11-2.05 (m, 1H), 1.85-1.67 (m, 3H).

Step B: benzyl(2S)-2-(cyanomethyl)-4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 749 μmol, 1.0 eq) in toluene (10 mL) was added m-CPBA (152 mg,749 μmol, 85% purity, 1.0 eq). The mixture was stirred at 0° C. for 1hour. The mixture was diluted with water (10 mL) and adjusted pH˜7 withsaturated NaHCO₃ aqueous solution. Then the mixture was extracted withethyl acetate (3×20 mL). The combined organic layers were washed withbrine (20 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give the product. Benzyl(2S)-2-(cyanomethyl)-4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(400 mg, 539 μmol, 72% yield, 92% purity) was obtained as a yellow solidand used next step directly without purification. LCMS [ESI, M+1]: 683.

Step C: benzyl(2S)-2-(cyanomethyl)-4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(350 mg, 512 μmol, 1.0 eq) in toluene (10 mL) was added it-BuONa (148mg, 1.54 mmol, 3.0 eq) and[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methanol (136 mg, 1.03 mmol,2.0 eq). The mixture was stirred at 0° C. for 0.5 hour. The reactionmixture was diluted with water (20 mL) and extracted with ethyl acetate(3×30 mL). The combined organic layers were washed with brine (20 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive a residue. The residue was purified by reverse phase flash [water(0.1% formic acid)/acetonitrile)] The mixture was adjusted pH˜7 withsaturated NaHCO₃ aqueous solution and extracted with ethyl acetate (3×50mL). The combined organic layers were washed with brine (20 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to givethe product. Benzyl(2S)-2-(cyanomethyl)-4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(280 mg, 372 μmol, 73% yield, 100% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 752.

Step C:2-[(2S)-4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(230 mg, 306 umol, 1.0 eq) in methanol (2.0 mL) was added dry Pd/C (50.0mg, 10% purity) and NH₃/methanol (1.00 mL, 20% purity) under N₂. Thesuspension was degassed under vacuum and purged with H₂ several times.The mixture was stirred under H₂ (15 psi) at 25° C. for 0.5 hour. Themixture was concentrated under vacuum.2-[(2S)-4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(180 mg, 285 μmol, 93% yield, 98% purity) was obtained as a yellow solidand used next step without purification. LCMS [ESI, M+1]: 618.

Step D:2-[(2S)-4-[7-(5,6-dimethyl-1H-indazol-4-yl)-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(30 mg, 48.6 μmol, 1.0 eq) in dichloromethane (300 uL) was added TFA(221 mg, 1.94 mmol, 144 μL, 40 eq). The mixture was stirred at 0° C. for0.5 hour. The mixture was concentrated under vacuum and diluted withwater (10 mL). The mixture was adjusted pH˜8 with saturated NaHCO₃aqueous solution and extracted with dichloromethane (3×20 mL). Thecombined organic layers were washed with brine (20 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give theproduct. The residue was purified by prep-HPLC (column: Xtimate C18150*25 mm*5 um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN];B %: 26%-56%, 1 min). The desired fraction was collected andlyophilized.2-[(2S)-4-[7-(5,6-dimethyl-1H-indazol-4-yl)-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(7.08 mg, 13.1 μmol, 27% yield, 98.5% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 534.

¹H NMR (400 MHz, chloroform-d) δ=10.14 (br s, 1H), 8.04 (d, J=0.8 Hz,1H), 7.14 (s, 1H), 5.32-5.03 (m, 1H), 4.44 (dd, J=4.4, 11.2 Hz, 1H),4.33-4.19 (m, 3H), 4.00 (br d, J=112.8 Hz, 1H), 3.82 (br d, J=12.0 Hz,1H), 3.65-3.41 (m, 3H), 3.27 (br d, J=6.4 Hz, 1H), 3.17-2.95 (m, 4H),2.90 (br dd, J=10.0, 12.4 Hz, 1H), 2.83-2.47 (m, 8H), 2.41 (s, 3H),2.38-2.23 (m, 4H), 2.09-1.90 (m, 1H).

Step E:2-[(2S)-4-[7-(5,6-dimethyl-1H-indazol-4-yl)-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(5,6-dimethyl-1H-indazol-4-yl)-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(100 mg, 187 μmol, 1.0 eq) and 2-fluoroprop-2-enoic acid (25.3 mg, 281μmol, 1.5 eq) in ethyl acetate (2.0 mL) was added T3P (477 mg, 749 μmol,446 μL, 50% purity in ethyl acetate, 4.0 eq) and TEA (114 mg, 1.12 mmol,156 μL, 6.0 eq) at 0° C. The mixture was stirred at 0° C. for 0.5 hour.The reaction mixture was diluted with water (20 mL) and extracted withethyl acetate (3×30 mL). The combined organic layers were washed withbrine (20 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by columnchromatography (SiO₂, Ethyl acetate/Methanol=100/1 to 10/1) and furtherpurification by prep-HPLC (column: Waters Xbridge 150*25 5 u; mobilephase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 38%-68%, 10 min).The desired fraction was collected and lyophilized.2-[(2S)-4-[7-(5,6-dimethyl-1H-indazol-4-yl)-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile(8 mg, 12.8 umol, 7% yield, 96.9% purity) was obtained as a white solid.LCMS [ESI, M+1]: 606.

¹H NMR (400 MHz, chloroform-d) δ=10.03 (br s, 1H), 8.04 (s, 1H), 7.15(s, 1H), 5.42 (dd, J=6.4 Hz, J=47.2 Hz 1H), 5.31-5.05 (m, 2H), 5.04-3.76(m, 9H), 3.65-3.47 (m, 3H), 3.42-3.25 (m, 1H), 3.20-2.70 (m, 6H)2.70-2.55 (m, 1H), 2.51 (s, 3H), 2.42 (s, 3H), 2.38-2.25 (m, 4H),2.10-1.87 (m, 1H).

Example 607

2-((S)-1-(2-fluoroacryloyl)-4-(7-(6-methylisoquinolin-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: tert-butyl(2S)-2-(cyanomethyl)-4-[7-(6-methyl-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.A mixture of tert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(250 mg, 530 μmol, 1.0 eq), 4-bromo-6-methyl-isoquinoline (235 mg, 1.06mmol, 2.0 eq), RuPhos (98.9 mg, 212 μmol, 0.4 eq), Pd₂(dba)₃ (97.1 mg,106 umol, 0.2 eq) and Cs₂CO₃ (432 mg, 1.33 mmol, 2.5 eq) in toluene (5mL) was degassed and purged with N₂ 3 times, and then the mixture wasstirred at 90° C. for 8 hours under N₂ atmosphere. The reaction mixturewas diluted with water (20 mL) and extracted with ethyl acetate (3×30mL). The combined organic layers were washed with brine (20 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by reverse phase flash [water (0.1%formic acid)/acetonitrile)]. The mixture was adjusted pH˜7 withsaturated NaHCO₃ aqueous solution and extracted with ethyl acetate (3×30mL). The combined organic layers were washed with brine (20 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to givethe product. tert-butyl(2S)-2-(cyanomethyl)-4-[7-(6-methyl-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(230 mg, 349 μmol, 66% yield, 93% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 613.

Step B:2-[(2S)-4-[7-(6-methyl-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-2-(cyanomethyl)-4-[7-(6-methyl-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(50 mg, 81.6 μmol, 1.0 eq) in dioxane (400 μL) was added HCl/dioxane (4M, 408 uL). The mixture was stirred at 25° C. for 0.3 hour. The mixturewas concentrated under vacuum and diluted with water (10 mL). Themixture was adjusted pH˜8 with saturated NaHCO₃ aqueous solution andextracted with dichloromethane (3×20 mL). The combined organic layerswere washed with brine (20 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give the residue. The residue waspurified prep-HPLC (column: Xtimate C18 150*25 mm*5 um; mobile phase:[water (0.05% ammonia hydroxide v/v)-ACN]; B %: 28%-58%, 1 min). Thedesired fraction was collected and lyophilized.2-[(2S)-4-[7-(6-methyl-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(19 mg, 37 μmol, 45% yield, 99.9% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 513.

¹H NMR (400 MHz, chloroform-d) δ=8.94 (s, 1H), 8.20 (s, 1H), 7.92-7.83(m, 2H), 7.45 (dd, J=1.2, 8.4 Hz, 1H), 4.40 (dd, J=4.8, 10.8 Hz, 1H),4.29 (s, 2H), 4.17 (dd, J=6.8, 10.8 Hz, 1H), 4.03 (br d, J=12.8 Hz, 1H),3.86 (br d, J=12.4 Hz, 1H), 3.42 (br t, J=5.2 Hz, 2H), 3.33-3.22 (m,1H), 3.17-2.80 (m, 7H), 2.72-2.63 (m, 1H), 2.61-2.52 (m, 5H), 2.47 (s,31H), 2.33-2.23 (m, 1H), 2.11-2.06 (m, 1H), 1.89-1.68 (m, 3H).

Step C:2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[7-(6-methyl-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(6-methyl-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(100 mg, 195 μmol, 1.0 eq) and 2-fluoroprop-2-enoic acid (35.1 mg, 390umol, 2.0 eq) in ethyl acetate (2 mL) was added T3P (372 mg, 585 μmol,348 μL, 50% purity in ethyl acetate, 3.0 eq) and TEA (158 mg, 1.56 mmol,217 μL, 8.0 eq) at 0° C. The mixture was stirred at 0° C. for 0.5 hour.The reaction mixture was diluted with water (20 mL) and extracted withethyl acetate (3×30 mL). The combined organic layers were washed withbrine (20 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by columnchromatography (SiO₂, Ethyl acetate/Methanol=100/1 to 10/1) and furtherpurification by prep-HPLC (column: Waters Xbridge 150*25 5 u: mobilephase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 38%-62%, 10 min).The desired fraction was collected and lyophilized.2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[7-(6-methyl-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(11 mg, 18.6 μmol, 9% yield, 98.9% purity) was obtained as a whitesolid. LCMS [ESI, M+1]: 585.

¹H NMR (400 MHz, chloroform-d) δ=8.96 (s, 1H), 8.22 (s, 1H), 7.93-7.85(m, 2H), 7.46 (dd, J=1.2, 8.4 Hz, 1H), 5.49-5.36 (m, 1H), 5.26 (dd,J=3.6, 16.8 Hz, 1H), 4.88 (br s, 1H), 4.50-4.29 (m, 3H), 4.27-3.96 (m,4H), 3.61-3.30 (m, 4H), 3.22-3.06 (m, 2H), 3.04-2.77 (m, 4H), 2.75-2.65(m, 1H), 2.59 (s, 3H), 2.49 (s, 3H), 2.31-2.29 (m, 1H), 2.15-1.97 (m,1H), 1.80-1.77 (m, 3H).

Example 608

2-[(2S)-4-[7-(8-ethyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile

Step A: tert-butyl(2S)-2-(cyanomethyl)-4-[7-(8-ethyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of tert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(240 mg, 508.91 μmol, 1 eq), t-BuONa (146.72 mg, 1.53 mmol, 3 eq),RuPhos (47.50 mg, 101.78 umol, 0.2 eq) and RuPhos Pd G3 (85.13 mg,101.78 μmol, 0.2 eq) in toluene (5 mL) was added1-bromo-8-ethyl-naphthalene (239.31 mg, 1.02 mmol, 2 eq). The mixturewas stirred at 90° C. for 12 hrs. The mixture was added water (10 mL)and extracted with ethyl acetate (10 mL×3). The organic layers was driedover Na₂SO₄, filtered and concentrated. The residue was purified byreverse phase flash HPLC (C18, 0.1% FA in water, 0-45% MeCN). Theproduct of tert-butyl(2S)-2-(cyanomethyl)-4-[7-(8-ethyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(113 mg, 180.57 μmol, 35.48% yield, 100% purity) was obtained as yellowsolid. LCMS [ESI, M+1]:626.

Step B:2-[(2S)-4-[7-(8-ethyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl(2S)-2-(cyanomethyl)-4-[7-(8-ethyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(103 mg, 164.59 μmol, 1 eq) in DCM (2 mL) was added TFA (2 mL) at 25° C.The reaction mixture was stirred at 25° C. for 0.5 hr. The reactionmixture was quenched by addition saturated NaHCO₃ aqueous (20 mL) at 25°C. until pH=8, and then extracted with ethyl acetate (3×10 mL). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure.2-[(2S)-4-[7-(8-ethyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(81 mg, crude) was obtained as white solid. LCMS [ESI, M+1]: 526.

1H NMR (400 MHz, chloroform-d) δ=7.66-7.55 (m, 2H), 7.37-7.25 (m, 2H),7.25-7.20 (m, 1H), 7.19-7.14 (m, 1H), 4.36-4.26 (m, 1H), 4.21-4.02 (m,2H), 4.00-3.62 (m, 3H), 3.56-2.73 (m, 11H), 2.65-2.34 (m, 7H), 2.26-2.14(m, 1H), 2.02-1.88 (m, 1H), 1.82-1.62 (m, 4H), 1.13-1.02 (m, 3H).

Step C:2-[(2S)-4-[7-(8-ethyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-ethyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(61 mg. 116.04 μmol, 1 eq) and 2-fluoroprop-2-enoic acid (20.90 mg,232.08 μmol, 2 eq) in DMF (10 mL) were added TEA (281.81 mg, 2.78 mmol,387.63 μL, 24 eq) and T3P (332.29 mg, 1.04 mmol, 310.55 uL, 9 eq) at−40° C. After addition, the mixture was stirred at 0° C. for 2 hrs. Themixture was diluted with water (3×20 mL) and diluted with ethyl acetate(3×20 mL). The organic layer was washed with brine (1×20 mL), dried overNa₂SO₄, filtered and concentrated under vacuum. The residue was purifiedby prep-HPLC (column: Waters Xbridge 150*25 5 u; mobile phase: [water(0.05% ammonia hydroxide v/v)-ACN]; B %: 55%-85%, 10 min). The mixturewas diluted with water (3×20 mL) and diluted with ethyl acetate (3×20mL). The organic layer was washed with brine (1-20 mL), dried overNa₂SO₄, filtered and concentrated under vacuum to give2-[(2S)-4-[7-(8-ethyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile(7 mg, 11.63 μmol, 10.02% yield, 99.3% purity) was obtained as yellowsolid. LCMS [ESI, M+1]: 598.

1H NMR (400 MHz, chloroform-d) δ=7.67-7.54 (m, 2H), 7.39-7.26 (m, 2H),7.25-7.20 (m, 1H), 7.15 (s, 1H), 5.45-5.24 (m, 1H), 5.23-5.12 (m, 1H),4.95-4.58 (m, 1H), 4.33-4.25 (m, 1H), 4.25-3.63 (m, 6H), 3.57-3.33 (m,3H), 3.21-2.49 (m, 10H), 2.44-2.35 (m, 3H), 2.27-2.15 (m, 1H), 2.03-1.90(m, 1H), 1.82-1.66 (m, 3H), 1.13-1.04 (m, 3H).

Example 609

2-[(2S)-4-[7-(6-fluoro-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile

Step A: benzyl(2S)-2-(cyanomethyl)-4-[7-(6-fluoro-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To the mixture of benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(400 mg, 791 μmol, 1.0 eq), 4-bromo-6-fluoro-isoquinoline (215 mg, 949μmol, 1.2 eq), Cs₂CO₃ (773 mg, 2.37 mmol, 3.0 eq) and RuPhos (148 mg,316 μmol, 0.4 eq) in toluene (10 mL) was added Pd₂(dba)₃ (145 mg, 158μmol, 0.2 eq) under N₂. The suspension was degassed under vacuum andpurged with N₂ several times. The mixture was stirred under N₂ at 90° C.for 10 hours. The reaction mixture tittered and the filtrate wasconcentrated under vacuum. The residue was purified by reverse phaseflash [water (0.1% FA)/acetonitrile]. The desired fractions werecollected and basified with solid NaHCO₃, concentrated under vacuum toremove MeCN and extracted with ethyl acetate (2×40 mL). The organiclayers were dried over Na₂SO₄ and concentrated under vacuum to givebenzyl(2S)-2-(cyanomethyl)-4-[7-(6-fluoro-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(140 mg, 204 μmol, 26% yield, 95% purity) as a yellow solid.

Step B:2-[(2S)-4-[7-(6-fluoro-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To the mixture of benzyl(2S)-2-(cyanomethyl)-4-[7-(6-fluoro-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(30 mg, 46.1 μmol, 1.0 eq) and NH₃·MeOH (0.3 mL, 20° % purity) in MeOH(0.3 mL) was added Pd/C (10 mg, 10% purity) under N₂. The suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred under H₂ (15 psi) at 25° C. for 1.5 hours. The reaction mixturewas filtered and the filtrate was concentrated under vacuum. The residuewas purified by prep-HPLC (column: Xtimate C18 150*25 mm*5 um; mobilephase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 30%-60%, 1 min).The desired fractions were collected and lyophilized to give2-[(2S)-4-[7-(6-fluoro-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(9.78 mg, 18.9 μmol, 41% yield, 99.9% purity) as a white solid. LCMS[ESI, M+1]: 517.

¹H NMR (400 MHz, chloroform-d) δ=9.00 (s, 1H), 8.27 (s, 1H), 8.02 (dd,J=5.6, 9.2 Hz, 1H), 7.74 (dd, J=2.4, 10.4 Hz, 1H), 7.39 (dt, J=2.4, 8.8Hz, 1H), 4.41 (dd, J=4.8, 10.4 Hz, 1H), 4.28 (s, 2H), 4.18 (dd, J=6.8,10.4 Hz, 1H), 4.02 (br d, J=12.4 Hz, 1H), 3.91-3.82 (m, 1H), 3.47-3.35(m, 2H), 3.33-3.24 (m, 1H), 3.18-3.07 (m, 3H), 3.07-2.97 (m, 1H), 2.93(dd, J=9.6, 12.8 Hz, 1H), 2.85 (br s, 2H), 2.73-2.64 (m, 1H), 2.56 (dd,J=2.4, 6.4 Hz, 2H), 2.49 (s, 3H), 2.34-2.24 (m, 1H), 2.13-2.00 (m, 1H),1.91-1.76 (m, 3H).

Step C:2-[(2S)-4-[7-(6-fluoro-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.To the mixture of2-[(2S)-4-[7-(6-fluoro-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(80 mg, 155 μmol, 1.0 eq), 2-fluoroprop-2-enoic acid (41.8 mg, 464 μmol,3.0 eq) and TEA (235 mg, 2.32 mmol, 323 uL, 15 eq) in ethyl acetate (1.5mL) and DMF (1 mL) was added T3P (493 mg, 774 μmol, 460 uL, 50% purity,5.0 eq) at 0° C., the mixture was stirred at 25° C. for 1 hour. Water(10 mL) was added into the mixture. The mixture was diluted with ethylacetate (30 mL) and extracted with ethyl acetate (2×5 mL). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by prep-HPLC(column: Xtimate C18 150*25 mm*5 um; mobile phase: [water (0.05% ammoniahydroxide v/v)-ACN]; B %: 40%-70%, 1 min). The desired fractions werecollected and lyophilized to give2-[(2S)-4-[7-(6-fluoro-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile(17.4 mg, 29.3 μmol, 19% yield, 99.2% purity) as a white solid. LCMS[ESI, M+1]: 589.

¹H NMR (400 MHz, chloroform-d) δ=9.01 (s, 1H), 8.28 (s, 1H), 8.03 (dd,J=5.6, 8.8 Hz, 1H), 7.73 (dd, J=2.4, 10.4 Hz, 1H), 7.40 (dt, J=2.4, 8.8Hz, 1H), 5.52-5.35 (m, 1H), 5.27 (dd, J=3.6, 17.2 Hz, 1H), 5.02-4.62 (m,1H), 4.46-4.38 (m, 1H), 4.36-4.25 (m, 2H), 4.24-4.07 (m, 3H), 4.02 (brd, J=13.2 Hz, 1H), 3.62-3.29 (m, 4H), 3.13 (br s, 2H), 3.03-2.93 (m,2H), 2.91-2.77 (m, 2H), 2.72 (br s, 1H), 2.51 (s, 3H), 2.32 (br d, J=8.4Hz, 1H), 2.13-2.02 (m, 1H), 1.92-1.70 (m, 3H).

Example 610

(S)-2-(1-(2-fluoroacryloyl)-4-(7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: tert-butyl4-hydroxy-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate. To amixture of O1-tert-butyl O4-ethyl 3-oxopiperidine-1,4-dicarboxylate(5.00 g, 18.4 mmol, 1.00 eq) in n-BuOH (30.0 mL) was added acetic acid;methanimidamide (9.59 g, 92.2 mmol, 5.00 eq) in portion. The mixture wasstirred at 120° C. for 12 hours. The mixture was concentrated to removethe solvent. The residue was added water (30.0 mL) and filtered. Theprecipitate was washed with water (30.0 mL) and concentrated. The crudeproduct was used in the next step directly without further purification.Compound tert-butyl4-hydroxy-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (4.10 g,16.1 mmol, 87% yield, 98.4% purity) was obtained as a brown solid. LCMS[ESI, M+1]: 196.

Step B: tert-butyl4-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate. To amixture of tert-butyl4-hydroxy-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (3.30 g,13.1 mmol, 1.00 eq) in DCE (60.0 mL) was added PPh₃ (6.89 g, 26.3 mmol,2.00 eq), CCl₄ (6.06 g, 39.4 mmol, 3.79 mL, 3.00 eq) in portion underN₂. The mixture was stirred at 70° C. for 3 hours. The reaction mixturewas filtered and concentrated under reduced pressure to give a residue.The residue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=20/1 to 1/1). Compound tert-butyl4-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (2.54 g,9.42 mmol, 72% yield, 100% purity) was obtained as a yellow solid. LCMS[ESI, M+1]: 214.

Step C: tert-butyl4-[(3S)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate.To a mixture of tert-butyl4-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (1.30 g,4.82 mmol, 1.00 eq) and benzyl(2S)-2-(cyanomethyl)piperazine-1-carboxylate (1.00 g, 3.86 mmol, 0.80eq) in DMAc (30.0 ML) was added DIEA (3.11 g, 24.1 mmol, 4.20 mL, 5.00eq) under N₂. The mixture was stirred at 100° C. for 2 hours. Thereaction mixture was diluted with ethyl acetate (100 mL). The organiclayers were washed with water (30 mL×2) and brine (30 mL×1), dried oversodium sulfate, filtered and concentrated under reduced pressure to givea residue. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=20/1 to 0/1). Compound tert-butyl4-[(3S)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(1.18 g, 2.30 mmol, 48% yield, 96% purity) was obtained as a whitesolid. LCMS [ESI, M+1]: 493.

Step D: benzyl(2S)-2-(cyanomethyl)-4-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate. To a mixture of tert-butyl4-[(3S)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(1.20 g, 2.44 mmol, 1.00 eq) in acetonitrile (10.0 mL) was addedHCl/dioxane (4.00 M, 12.2 mL, 20.0 eq) in portion at 25° C. under N₂.The mixture was stirred at 25° C. for 30 min. The reaction mixture wasconcentrated under reduced pressure to give a residue. The crude productwas used in the next step directly without further purification.Compound benzyl(2S)-2-(cyanomethyl)-4-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (883 mg, 2.16 mmol, 89% yield, 96% purity) wasobtained as a yellow solid. LCMS [ESI, M+1]: 393.

Step E: benzyl(2S)-2-(cyanomethyl)-4-[7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a mixture of benzyl(2S)-2-(cyanomethyl)-4-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(300 mg, 764 μmol, 1.00 eq) and 1-bromonaphthalene (317 mg, 1.53 mmol,212 uL, 2.00 eq) in toluene (15.0 mL) was added Pd₂(dba)₃ (140 mg, 153μmol, 0.20 eq), RuPhos (143 mg, 306 μmol, 0.40 eq) Cs₇CO₃ (747 mg, 2.29mmol, 3.00 eq) in one portion under N₂. The mixture was stirred at 90°C. for 5 hours. The reaction mixture was diluted with water (10.0 mL)and extracted with ethyl acetate (20.0 mL×3). The combined organiclayers were washed with brine (20.0 mL×1), dried over sodium sulfate,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by reversed phase flash [water (0.1%FA)/acetonitrile]. The desired fractions were collected and neutralizedwith saturated NaHCO₃ solution (5.00 mL) and extracted with ethylacetate (50.0 mL×2). The separated organic layer was dried over sodiumsulfate, filtered and concentrated under vacuum Compound benzyl(2S)-2-(cyanomethyl)-4-[7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(150 mg, 289 μmol, 38% yield) was obtained as a yellow solid.

Step F:2-[(2S)-4-[7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(50.0 mg, 96.4 μmol, 1.00 eq) in MeOH (3.00 mL) was added Pd/C (30.0 mg,10% purity), NH₃-MeOH (0.50 mL, 20% purity) under N₂. The suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred under H₂ (15 psi) at 25° C. for 1 hour. The reaction mixture wasfiltered and concentrated under reduced pressure to give a residue. Theresidue was purified by prep-HPLC (column: Waters Xbridge 150×25 5 u;mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN], B %: 35%-59%,10 min). Compound2-[(2S)-4-[7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(8.63 mg, 22.4 μmol, 23% yield, 99.8% purity) was obtained as aoff-white solid. LCMS [ESI, M+1]: 385.

¹H NMR (400 MHz, chloroform-d) δ=8.63 (s, 1H), 8.26-8.19 (m, 1H),7.91-7.84 (m, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.54-7.48 (m, 2H), 7.45 (t,J=7.6 Hz, 1H), 7.17 (d, J=7.2 Hz, 1H), 4.35 (s, 2H), 3.99 (br d, J=12.8Hz, 1H), 3.83 (br d, J=12.8 Hz, 1H), 3.53-3.23 (m, 3H), 3.20-3.07 (m,2H), 3.07-2.90 (m, 4H), 2.63-2.49 (m, 2H).

Step G: To a mixture of2-[(2S)-4-[7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(60.0 mg, 156 μmol, 1.00 eq) in ethyl acetate (0.60 mL) was added2-fluoroprop-2-enoic acid (56.2 mg, 624 μmol, 4.00 eq), TEA (253 mg,2.50 mmol, 348 uL, 16.0 eq) and T3P (596 mg, 936 μmol, 557 uL, 50%purity, 6.00 eq) in portion at 0° C. under N₂. The mixture was stirredat 25° C. for 30 min. The reaction mixture was quenched by additionwater (1.00 mL) at 0° C., and then extracted with ethyl acetate (10.0mL×3). The combined organic layers were washed with brine (5.00 mL×1),dried over sodium sulfate, filtered and concentrated under reducedpressure to give a residue. The residue was purified by prep-HPLC(column: Waters Xbridge 150×25 5 u; mobile phase: [water (0.05% ammoniahydroxide v/v)-ACN]: B %: 40%-70%, 10 min). Compound2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(15.2 mg, 32.8 μmol, 21% yield, 98.9% purity) was obtained as a whitesolid. LCMS [ESI, M+1]: 457.

¹H NMR (400 MHz, chloroform-d) δ=8.67 (s, 1H), 8.26-8.18 (m, 1H),7.91-7.84 (m, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.56-7.49 (m, 2H), 7.45 (t,J=7.6 Hz, 1H), 7.18 (d, J=8 Hz, 1H), 5.54-5.34 (m, 1H), 5.27 (dd, J=4.0,17.2 Hz, 1H), 4.91 (br s, 1H), 4.46-4.29 (m, 2H), 4.14 (br d, J=13.6 Hz,1H), 3.99 (br d, J=13.2 Hz, 1H), 3.63-3.32 (m, 4H), 3.16 (br t, J=11.2Hz, 2H), 2.99 (br dd, J=8.0, 16.4 Hz, 3H), 2.90-2.77 (m, 1H).

Example 611

(S)-2-(1-(2-fluoroacryloyl)-4-(7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a mixture of benzyl(2S)-2-(cyanomethyl)-4-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(100 mg, 255 μmol, 1.00 eq) and 1-bromo-8-methyl-naphthalene (113 mg,510 μmol, 10.6 uL, 2.00 eq) in toluene (8.00 mL) was added Pd₂(dba)₃(46.7 mg, 51.0 μmol, 0.20 eq), RuPhos (47.6 mg, 102 μmol, 0.40 eq)Cs₂CO₃ (249 mg, 764 μmol, 3.00 eq) in one portion under N₂. The mixturewas stirred at 90° C. for 5 hours. The reaction mixture was diluted withwater (10.0 ml) and extracted with ethyl acetate (20.0 mL×3). Thecombined organic layers were washed with brine (20.0 mL×1), dried oversodium sulfate, filtered and concentrated under reduced pressure to givea residue. The residue was purified by reversed phase flash [water (0.1%FA)/acetonitrile]. The desired fractions were collected and neutralizedwith saturated NaHCO₃ solution (5.00 ml) and extracted with ethylacetate (50.0 mL×2). The separated organic layer was dried over sodiumsulfate, filtered and concentrated under vacuum. Compound benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(150 mg, crude) was obtained as a yellow solid.

Step B:2-[(2S)-4-[7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of benzyl(2S)-2-cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(50.0 mg, 93.9 μmol, 1.00 eq) in methanol (1.00 mL) was added NH₃·MeOH(93.9 μmol, 0.2 mL, 20% purity, 1.00 eq), Pd/C (15.0 mg, 10% purity)under N₂. The suspension was degassed under vacuum and purged with H₂several times. The mixture was stirred under H₂ (15 psi) at 25° C. for 1hour. The reaction mixture was filtered and concentrated under reducedpressure to give a residue. The residue was purified by prep-HPLC(column: Waters Xbridge 150*25 5 u; mobile phase: [water (0.05% ammoniahydroxide v/v)-ACN]; B %: 38%-62%, 10 min). Compound2-[(2S)-4-[7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(6.13 mg, 15.3 μmol, 16% yield, 99.5% purity) was obtained as a whitesolid. LCMS [ESI, M+1]: 399.

¹H NMR (400 MHz, chloroform-d) δ=8.61 (d, J=4.8 Hz, 1H), 7.74-7.63 (m,2H), 7.41 (dt, J=2.8, 7.6 Hz, 1H), 7.37-7.31 (m, 1H), 7.27-7.22 (m, 2H),4.32 (br d, J=18.0 Hz, 1H), 4.07-3.92 (m, 1H), 3.92-3.86 (m, 1H),3.86-3.67 (m, 1H), 3.56-3.48 (m, 1H), 3.30-3.24 (m, 1H), 3.24-3.18 (m,1H), 3.18-2.96 (m, 4H), 2.94 (d, J=2.4 Hz, 3H), 2.92 (br s, 1H),2.92-2.83 (m, 1H), 2.69-2.59 (m, 1H), 2.57-2.53 (m, 2H).

Step C:2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a mixture of2-[(2S)-4-[7-(8-methyl-1-naphthyl)-6,8-dihydro-1-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(60.0 mg, 151 μmol, 1.00 eq) in ethyl acetate (1.00 mL) was added2-fluoroprop-2-enoic acid (54.2 mg, 602 μmol, 4.00 eq), TEA (244 mg,2.41 mmol, 335 uL, 16.0 eq) and T3P (575 mg, 903 μmol, 537 uL, 50%purity, 6.00 eq) in portion at 0° C. under N₂. The mixture was stirredat 25° C. for 30 min. The reaction mixture was quenched by additionwater (1.00 mL) at 0° C., and then extracted with ethyl acetate (10mL×3). The combined organic layers were washed with brine (5 mL×1),dried over sodium sulfate, filtered and concentrated under reducedpressure to give a residue. The residue was purified by prep-HPLC(column: Waters Xbridge 150×25 5 u; mobile phase: [water (0.05% ammoniahydroxide v/v)-ACN]; B %: 40%-70%, 10 min). Compound2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(8.97 mg, 18.7 μmol, 12% yield, 98.2% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 492.

¹H NMR (400 MHz, chloroform-d) δ=8.64 (d, J=7.2 Hz, 1H), 7.74-7.64 (m,2H), 7.47-7.39 (m, 1H), 7.39-7.32 (m, 1H), 7.29 (br d, J=1.2 Hz, 1H),7.26-7.19 (m, 1H), 5.53-5.33 (m, 1H), 5.26 (dd, J=3.6, 17.2 Hz, 1H),4.87 (br s, 1H), 4.33 (br dd, J=14.8, 18.0 Hz, 1H), 4.19 (br d, J=13.61Hz, 1H), 4.12-3.97 (m, 2H), 3.95-3.84 (m, 1H), 3.61-3.42 (m, 2H),3.27-3.04 (m, 4H), 2.92 (d, J=2.4 Hz, 3H), 2.89-2.62 (m, 3H).

Example 612

(S)-2-(4-(7-(5-chloroisoquinolin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

Step A: benzyl(2S)-4-[7-(5-chloro-4-isoquinolyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.To a mixture of benzyl(2S)-2-(cyanomethyl)-4-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(300 mg, 764 μmol, 1.00 eq) and 4-bromo-5-chloro-isoquinoline (371 mg,1.53 mmol, 10.6 μL, 2.00 eq) in toluene (15.0 mL) was added Pd₂(dba)₃(140 mg, 153 μmol, 0.20 eq), RuPhos (143 mg, 306 μmol, 0.40 eq), Cs₂CO₃(747 mg, 2.29 mmol, 3.00 eq) in one portion under N₂. The mixture wasdegassed and purged with N₂ 3 times and stirred at 90° C. for 5 hours.The reaction mixture was diluted with water (10.0 mL) and extracted withethyl acetate (20.0 mL×3). The combined organic layers were washed withbrine (20.0 mL×1), dried over sodium sulfate, filtered and concentratedunder reduced pressure to give a residue. The residue was purified byreversed phase flash [water (0.1% FA)/acetonitrile]. The desiredfractions were collected and neutralized with saturated NaHCO₃ solution(5 mL) and extracted with ethyl acetate (50 mL×2). The separated organiclayer was dried over sodium sulfate, filtered and concentrated undervacuum. Compound benzyl(2S)-4-[7-(5-chloro-4-isoquinolyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(130 mg, 223 μmol, 29% yield, 95% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 554.

Step B:2-[(2S)-4-[7-(5-chloro-4-isoquinolyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of benzyl(2S)-4-[7-(5-chloro-4-isoquinolyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(30.0 mg, 54.2 μmol, 1.00 eq) in methanol (3.00 mL) was added NH₃·MeOH(0.50 mL, 20% purity), Pd/C (35.0 mg, 10% purity) under N₂. Thesuspension was degassed under vacuum and purged with H₂ several times.The mixture was stirred under H₂ (15 psi) at 25° C. for 1 hour. Thereaction mixture was filtered and concentrated under reduced pressure togive a residue. The residue was purified by prep-HPLC (column: WatersXbridge 150×25 5 u; mobile phase: [water (0.05% ammonia hydroxidev/v)-ACN]; B %: 22%-46%, 10 min). Compound2-[(2S)-4-[7-(5-chloro-4-isoquinolyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(8.51 mg, 20.1 μmol, 37% yield, 99.4% purity) was obtained as a whitesolid. LCMS [ESI, M+1]: 420.

¹H NMR (400 MHz, chloroform-d) δ=9.02 (s, 1H), 8.60 (d, J=4.4 Hz, 1H),8.35 (d, J=1.6 Hz, 1H), 7.91 (dd, J=1.2, 8.4 Hz, 1H), 7.75 (dd, J=1.2,7.2 Hz, 1H), 7.50 (t, J=7.6 Hz, 1H), 4.54 (br d, J=17.2 Hz, 1H),4.06-3.61 (m, 4H), 3.41-3.08 (m, 5H), 3.07-2.85 (m, 2H), 2.72-2.59 (m,1H), 2.58-2.49 (m, 2H).

Step C:2-[(2S)-4-[7-(5-chloro-4-isoquinolyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.To a mixture of2-[(2S)-4-[7-(5-chloro-4-isoquinolyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(60.0 mg, 143 μmol, 1.00 eq) in ethyl acetate (0.80 mL) was added2-fluoroprop-2-enoic acid (25.7 mg, 286 μmol, 2.00 eq), TEA (86.8 mg,857 μmol, 119 uL, 6.00 eq) and T3P (273 mg, 429 μmol, 255 uL, 50%purity, 3.00 eq) in portion at 0° C. under N₂. The mixture was stirredat 25° C. for 30 min. The reaction mixture was quenched by additionwater (1.00 mL) at 0° C., and then extracted with ethyl acetate (10.0mL×3). The combined organic layers were washed with brine (5.00 mL×1),dried over sodium sulfate, filtered and concentrated under reducedpressure to give a residue. The residue was purified by prep-HPLC(column: Waters Xbridge 150×25 5 u; mobile phase: [water (0.05% ammoniahydroxide v/v)-ACN]; B %: 22%-52%, 10 min). Compound2-[(2S)-4-[7-(5-chloro-4-isoquinolyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile(7.88 mg, 16.0 μmol, 11% yield, 100% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 492.

¹H NMR (400 MHz, chloroform-d) δ=9.04 (d, J=3.6 Hz, 1H), 8.65 (d, J=6.4Hz, 1H), 8.35 (d, J=11.6 Hz, 1H), 7.96-7.88 (m, 1H), 7.76 (dd, J=1.2,7.2 Hz, 1H), 7.56-7.47 (m, 1H), 5.55-5.33 (m, 1H), 5.26 (dd, J=3.2, 16.8Hz, 1H), 5.03-4.70 (m, 1H), 4.55 (br dd, J=6.4, 18.0 Hz, 1H), 4.23-3.84(m, 4H), 3.69 (br d, J=6.4 Hz, 1H), 3.50 (br d, J=13.6 Hz, 1H),3.35-3.19 (m, 3H), 3.16-3.00 (m, 1H), 2.97-2.61 (m, 3H).

Example 613

2-((S)-4-(2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6-dimethyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

Step A: benzyl(2S)-2-(cyanomethyl)-4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.A mixture of benzyl(2S)-2-(cyanomethyl)-4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(5.0 g, 11.4 mmol, 1.0 eq),4-bromo-5,6-dimethyl-1-tetrahydropyran-2-yl-indazole (7.05 g, 22.8 mmol,2.0 eq), Pd₂(dba)₃ (2.09 g, 2.28 mmol, 0.2 eq), RuPhos (2.13 g, 4.56mmol, 0.4 eq) and Cs₂CO₃ (9.29 g, 28.5 mmol, 2.5 eq) in toluene (100 mL)was degassed and purged with N₂ for 3 times, and then the mixture wasstirred at 90° C. for 8 hours under N₂ atmosphere. The reaction mixturewas diluted with water (100 mL) and extracted with ethyl acetate (3×200mL). The combined organic layers were washed with brine (100 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate:=20/1 to 2/1) and further purified byreverse phase flash [water (0.1% formic acid)/acetonitrile)]. Themixture was adjusted pH˜7 with saturated NaHCO₃ aqueous solution andextracted with ethyl acetate (3 100 mL). The combined organic layerswere washed with brine (50 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give the product. benzyl(2S)-2-(cyanomethyl)-4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(4.90 g, 7.20 mmol, 63% yield, 98% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 667.

¹H NMR (400 MHz, chloroform-d) δ=7.98 (s, 1H), 7.50-7.31 (m, 5H), 7.22(s, 1H), 5.66 (dd, J=2.4, 9.6 Hz, 1H) 5.27-5.13 (m, 2H), 4.69 (br s,1H), 4.27 (s, 2H), 4.13-3.97 (m, 3H), 3.89 (d, J=11.6 Hz, 1H), 3.81-3.68(m, 1H), 3.51 (t, J=5.2 Hz, 2H), 3.30 (br s, 2H), 3.04 (t, J=11.6 Hz,1H), 2.93-2.66 (m, 4H), 2.62-2.48 (m, 4H), 2.43 (s, 3H), 2.32 (s, 3H),2.23-2.12 (m, 1H), 2.11-2.05 (m, 1H), 1.85-1.67 (m, 3H).

Step B: benzyl(2S)-2-(cyanomethyl)-4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 749 μmol, 1.0 eq) in toluene (10 mL) was added m-CPBA (152 mg,749 μmol, 85% purity, 1.0 eq). The mixture was stirred at 0° C. for 1hour. The mixture was diluted with water (10 mL) and adjusted pH˜7 withsaturated NaHCO₃ aqueous solution. Then the mixture was extracted withethyl acetate (3×20 mL). The combined organic layers were washed withbrine (20 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give the product. Benzyl(2S)-2-(cyanomethyl)-4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(400 mg, 539 μmol, 72% yield, 92% purity) was obtained as a yellow solidand used next step directly without purification. LCMS [ESI, M+1]: 683.

Step C: benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(900 mg, 1.32 mmol, 1.0 eq) in toluene (20 mL) was added t-BuONa (379mg, 3.95 mmol, 3.0 eq) and[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methanol (398 mg, 2.64 mmol,2.0 eq). The mixture was stirred at 0° C. for 0.5 hour. The reactionmixture was diluted with water (30 mL) and extracted with ethyl acetate(3×50 mL). The combined organic layers were washed with brine (20 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive a residue. The residue was purified by column chromatography (SiO₂,Ethyl acetate/Methanol=100/1 to 10/1). Benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(630 mg, 793 μmol, 60% yield, 97% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 770.

Step D:2-[(2S)-4-[2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(400 mg, 519 μmol, 1.0 eq) in methanol (2 mL) was added dry Pd/C (50 mg,10% purity) and NH₃/methanol (1 mL, 20% purity) under N₂. The suspensionwas degassed under vacuum and purged with H₂ several times. The mixturewas stirred under H₂ (15 psi) at 25° C. for 0.5 hour. The mixture wasconcentrated under vacuum.2-[(2S)-4-[2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(330 mg, 519 μmol, 99% yield) was obtained as a yellow solid and usednext step directly without purification. LCMS [ESI, M+1]: 636.

Step E:2-[(2S)-4-[2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(5,6-dimethyl-1H-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(50 mg, 78.6 μmol, 1.0 eq) in dichloromethane (50 uL) was added TFA (359mg, 3.15 mmol, 233 μL, 40 eq). The mixture was stirred at 0° C. for 0.5hour. The mixture was concentrated under vacuum and diluted with water(10 mL). The mixture was adjusted pH˜8 with saturated NaHCO₃ aqueoussolution and extracted with dichloromethane (3×20 mL). The combinedorganic layers were washed with brine (20 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give the product.The residue was purified by column chromatography (SiO₂, Ethylacetate/Methanol=100/1 to 10/1) and further purification by prep-HPLC(column: Waters Xbridge 150*25 5 u; mobile phase: [water (0.05% ammoniahydroxide v/v)-ACN]; B %: 30%-60%, 10 min). The desired fraction wascollected and lyophilized2-[(2S)-4-[2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(5,6-dimethyl-1H-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(7.29 mg, 13.2 μmol, 17% yield, 99.7% purity) was obtained as a whitesolid. LCMS [ESI, M+1]: 552.

¹H NMR (400 MHz, chloroform-d) δ=9.95 (br s, 1H), 8.04 (s, 1H), 7.15 (s,1H), 4.48 (dd, J=4.4, 10.8 Hz, 1H), 4.33-4.19 (m, 3H), 4.00 (br d,J=11.6 Hz, 1H), 3.83 (br d, J=11.6 Hz, 1H), 3.51 (t, J=5.2 Hz, 2H), 3.42(dt, J=5.6, 11.7 Hz, 1H), 3.26 (br s, 1H), 3.17-2.95 (m, 4H), 2.94-2.85(m, 1H), 2.84-2.62 (m, 3H), 2.61-2.49 (m, 3H), 2.47 (s, 3H), 2.42 (s,3H), 2.35 (s, 3H), 2.32-2.18 (m, 1H).

Step F:2-[(2S)-4-[2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(5,6-dimethyl-1H-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(5,6-dimethyl-1H-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile1100 mg, 181 μmol, 1.0 eq) and 2-fluoroprop-2-enoic acid (24.5 mg, 272μmol, 1.5 eq) in DMF (2 mL) was added T3P (461 mg, 725 μmol, 431 μL, 50%purity in ethyl acetate, 4.0 eq) and TEA (147 mg, 1.45 mmol, 202 uL, 8.0eq) at 0° C. The mixture was stirred at 0° C. for 0.5 hour. The reactionmixture was diluted with water (20 mL) and extracted with ethyl acetate(3×30 mL). The combined organic layers were washed with brine (20 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive a residue. The residue was purified by column chromatography (SiO₂,Ethyl acetate/Methanol=100/1 to 10/1) and further purification byprep-HPLC (column: Waters Xbridge 150*25 5 u; mobile phase: [water(0.05% ammonia hydroxide v/v)-ACN]; B %: 38%-68%, 10 min). The desiredfraction was collected and lyophilized.2-[(2S)-4-[2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(5,6-dimethyl-1H-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile(11 mg, 17.5 μmol, 10% yield, 99.2% purity, 100% cc) was obtained as aoff-white solid. LCMS [ESI, M+1]: 624.

¹H NMR (400 MHz, chloroform-d) δ=10.27-9.49 (s, 1H), 8.04 (s, 1H), 7.16(s, 1H), 5.55-5.34 (m, 1H), 5.26 (dd, J=3.6, 16.8 Hz, 1H), 4.86 (br s,1H), 4.46 (dd, J=4.8, 10.8 Hz, 1H), 4.34-3.88 (m, 6H), 3.66-3.25 (m,5H), 3.19-2.62 (m, 7H), 2.60-2.45 (m, 4H), 2.42 (s, 3H), 2.35 (s, 3H),2.32-2.19 (m, 1H).

Example 614

2-((S)-4-(2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6-dimethyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((E)-4-fluorobut-2-enoyl)piperazin-2-yl)acetonitrile

Step A:2-[(2S)-4-[2-[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(5,6-dimethyl-1H-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-fluorobut-2-enoyl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(5,6-dimethyl-1H-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(100 mg, 181 μmol, 1.0 eq) and (E)-4-fluorobut-2-enoic acid (28.3 mg,272 μmol, 1.5 eq) in DMF (2 mL) was added T3P (461 mg, 725 μmol, 431 uL,50% purity in ethyl acetate, 4.0 eq) and TEA (147 mg, 1.45 mmol, 202 uL,8.0 eq) at 0° C. The mixture was stirred at 0° C. for 0.5 hour. Thereaction mixture was diluted with water (20 mL) and extracted with ethylacetate (3×30 mL). The combined organic layers were washed with brine(20 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue. The residue was purified by columnchromatography (SiO₂, Ethyl acetate/Methanol=100/1 to 10/1) and furtherpurification by prep-HPLC (column: Xtimate C18 150*25 mm*5 um; mobilephase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 40%-70%, 10 min).The desired fraction was collected and lyophilized.2-[(2S)-4-[2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-(5,6-dimethyl-1H-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[(E)-4-fluorobut-2-enoyl]piperazin-2-yl]acetonitrile(12 mg, 18.3 μmol, 10% yield, 97.3% purity, 95% ee) was obtained as awhite solid. LCMS [ESI, M+1]: 638.

¹H NMR (400 MHz, chloroform-d) δ=10.06 (br s, 1H), 8.05 (s, 1H), 7.17(s, 1H), 7.07-6.97 (m, 1H), 6.61 (br d, J=14.8 Hz, 1H), 5.20-5.07 (m,3H), 4.48 (dd, J=4.8, 11.2 Hz, 1H), 4.31-4.27 (m, 3H), 4.20-3.80 (m,3H), 3.55 (br t, J=5.2 Hz, 3H), 3.49-3.27 (m, 2H), 3.13 (br s, 1H),3.05-2.63 (m, 6H), 2.62-2.46 (m, 4H), 2.43 (s, 3H), 2.36 (s, 3H),2.33-2.21 (m, 1H).

Example 615

2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1,4,4-trimethylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

Step A: benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1,4,4-trimethylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of [(2S)-1,4,4-trimethylpyrrolidin-2-yl]methanol (217 mg,1.51 mmol, 68.2 μL, 3 eq) and benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(300 mg, 504 μmol, 1 eq) in toluene (15 mL) was added t-BuONa (145 mg,1.51 mmol, 3 eq) at 0° C. The mixture was stirred at 0° C. for 0.5 hour.Upon completion, the mixture was quenched with water (10 mL) andextracted with ethyl acetate (2×50 mL). The combined organic layers werewashed with brine (1×50 mL), dried over Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by reverse phaseflash [water (0.1% FA)/acetonitrile]. The desired fractions werecollected and neutralized with saturated Na₂CO₃ solution (10 mL) andextracted with ethyl acetate (3×50 mL). The separated organic layerswere dried over sodium sulfate, filtered and concentrated under vacuum.Benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1,4,4-trimethylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(180 mg, 267 μmol, 53% yield, 99.8% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 675.

¹H NMR (400 MHz, chloroform-d) δ=7.73-7.60 (m, 2H), 7.27 (s, 9H), 5.21(s, 2H), 4.68 (br s, 1H), 4.47-4.34 (m, 1H), 4.30-4.15 (m, 2H),4.13-4.04 (m, 1H), 3.95-3.69 (m, 2H), 3.56-3.34 (m, 2H), 3.28-2.48 (m,13H), 2.47-2.33 (m, 3H), 2.22-2.11 (m, 1H), 1.88 (br dd, J=8.4, 12.6 Hz,1H), 1.56 (ddd, J=4.6, 7.8, 12.6 Hz, 1H), 1.16 (d, J=4.0 Hz, 3H),1.10-0.98 (m, 3H).

Step B: 2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1,4,4-trimethylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1,4,4-trimethylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(130 mg, 193 μmol, 1 eq) in MeOH (4 mL) was added NH₃·MeOH (2 mL, 15%purity) and Pd/C (26 mg, 10% purity) under N₂. The suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred under H₂ (15 psi) at 25° C. for 0.5 hour. Upon completion, themixture was filtered and the filtrate was concentrated under vacuum.2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1,4,4-trimethylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(100 mg, 159 μmol, 85.9% purity) was obtained as a yellow solid whichwas used into next step without further purification. LCMS [ESI, M+1]:540.

Step C:2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1,4,4-trimethylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1,4,4-trimethylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido(3,4-d]pyrimidin-4-yl)piperazin-2-yl]acetonitrile(90 mg, 143 μmol, 1 eq), 2-fluoroprop-2-enoic acid (38.7 mg, 430 μmol, 3eq) and Et₃N (130 mg, 1.29 mmol, 179 uL, 9 eq) in ethyl acetate (15 mL)was added T3P (365 mg, 573 μmol, 341 uL, 50% purity in ethyl acetate, 4eq) at 0° C. The mixture was stirred at 0° C. for 1 hour. Uponcompletion, the mixture was diluted with water (3 mL). The organic layerwas separated, washed with brine (1×10 mL), dried over sodium sulfate,filtered and concentrated under vacuum. The mixture was purified bycolumn chromatography (SiO₂, ethyl acetate/methanol=20/1 to 10/1). Theresidue was purified by prep-HPLC (column: Waters Xbridge 150*25 5 u;mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 62%-89%,10 min). The residue was concentrated under reduced pressure to removeACN, and then lyophilization.2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[7-(8-methyl-1-naphthyl)-2-[[(2S)-1,4,4-trimethylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(12.7 mg, 20.6 μmol, 99.7% purity) was obtained as a white solid. LCMS[ESI, M+1]: 612.

¹H NMR (400 MHz, chloroform-d) δ=7.79-7.56 (m, 2H), 7.51-7.31 (m, 2H),7.27-7.08 (m, 2H), 5.65-5.08 (m, 2H), 4.85 (br s, 1H), 4.49-4.32 (m,1H), 4.30-3.96 (m, 4H), 3.95-3.71 (m, 1H), 3.59-3.35 (m, 2H), 3.28-2.54(m, 13H), 2.42 (br s, 3H), 2.16 (br d, J=8.8 Hz, 1H), 1.96-1.81 (m, 1H),1.63-1.45 (m, 1H), 1.15 (br s, 3H), 1.06 (br s, 3H).

Example 616

2-[(2S)-4-[2-[[(2S,4S)-1,4-dimethylpyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile

Step A: benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S,4S)-1,4-dimethylpyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of [(2S,4S)-1,4-dimethylpyrrolidin-2-yl]methanol (326 mg,2.52 mmol, 68.2 uL, 3 eq) and benzyl(2S)-2-(cyanomethyl)-4-[7-(8-methyl-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 841 μmol, 1 eq) in toluene (20 mL) was added t-BuONa (242 mg,2.52 mmol, 3 eq) at 0° C. The mixture was stirred at 0° C. for 0.5 hour.Upon completion, the mixture was quenched with water (10 mL) andextracted with ethyl acetate (2×20 mL). The combined organic layers werewashed with brine (1×20 mL), dried over Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by reverse phaseHPLC (0.1% FA condition). The residue was basified with saturatedaqueous NaHCO₃ solution to pH=8 and extracted with ethyl acetate (3×50mL). The organic phase was separated, dried over sodium sulfate,filtered and concentrated under vacuum. benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S,4S)-1,4-dimethylpyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(328 mg, 461 μmol, 55% yield, 92.7% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 661.

Step B:2-[(2S)-4-[2-[[(2S,4S)-1,4-dimethylpyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S,4S)-1,4-dimethylpyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(100 mg, 151 μmol, 1 eq) in MeOH (4 mL) was added NH₃-MeOH (2 mL, 20%purity) and Pd/C (20 mg, 10% purity) under N₂. The suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred under H₂ (15 psi) at 25° C. for 0.5 hour. Upon completion, themixture was filtered and the filtrate was concentrated under vacuum. Theresidue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*30mm*4 um; mobile phase: [water (0.225% FA)-ACN]; B %: 13%-43%, 10 min).After that, the residue was purified by prep-HPLC (column: WatersXbridge 150*25 5 u; mobile phase: [water (0.05% ammonia hydroxidev/v)-ACN]; B %: 55%-85%, 10 min). The residue was concentrated underreduced pressure to remove ACN, and then lyophilization.2-[(2S)-4-[2-[[(2S,4S)-1,4-dimethylpyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(13.9 mg, 26.4 μmol, 17% yield, 100% purity) was obtained as a whitesolid. LCMS [ESI, M+1]: 526.

¹H NMR (400 MHz, chloroform-d) δ=7.69 (d, J=8.2 Hz, 1H), 7.64 (dd,J=2.6, 7.6 Hz, 1H), 7.40 (dt, J=4.0, 7.8 Hz, 1H), 7.36-7.31 (m, 1H),7.26-7.19 (m, 2H), 4.43 (dt, J=4.8, 10.2 Hz, 1H), 4.28-4.11 (m, 2H),4.07-3.70 (m, 3H), 3.48 (br d, J=11.8 Hz, 1H), 3.38-2.82 (m, 1H),2.80-2.64 (m, 2H), 2.61-2.53 (m, 3H), 2.49 (t, J=8.6 Hz, 1H), 2.42 (d,J=2.4 Hz, 3H), 2.35-2.15 (m, 2H), 1.39-1.25 (m, 1H), 1.08 (d, J=6.8 Hz,3H).

Step C:2-[(2S)-4-[2-[[(2S,4S)-1,4-dimethylpyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.To a solution of 2-[(2S)-4-[2-[[(2S,4S)-1,4-dimethylpyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(100 mg, 190 μmol, 1 eq), 2-fluoroprop-2-enoic acid (51.4 mg, 571 μmol,3 eq) and Et₃N (173 mg, 1.71 mmol, 238 uL, 9 eq) in DMF (10 mL) wasadded T3P (484 mg, 761 μmol, 452 uL, 50% purity, 4 eq) at 0° C. Themixture was stirred at 0° C. for 0.5 hour. Upon completion, the residuewas diluted with water (10 mL) and extracted with ethyl acetate (2×20mL). The combined organic layers were washed with brine (1×20 mL), driedover sodium sulfate, filtered and concentrated under vacuum. The mixturewas purified by column chromatography (SiO₂,Dichloromethane/Methanol=10/1). After that, the residue was purified byprep-HPLC (column: Xtimate C18 150*25 mm*5 um; mobile phase: [water(0.05% ammonia hydroxide v/v)-ACN]; B %: 60%-90%, 10 min). The residuewas concentrated under reduced pressure to remove ACN, and thenlyophilization.2-[(2S)-4-[2-[[(2S,4S)-1,4-dimethylpyrrolidin-2-yl]methoxy]-7-(8-methyl-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile(22.2 mg, 37.1 μmol, 19% yield, 99.8% purity) was obtained as a whitesolid. LCMS [ESI, M+1]: 598.

¹H NMR (400 MHz, chloroform-d) δ=7.72-7.61 (m, 2H), 7.45-7.37 (m, 1H),7.37-7.31 (m, 1H), 7.26-7.17 (m, 2H), 5.53-5.32 (m, 1H), 5.26 (dd,J=3.6, 16.8 Hz, 1H), 4.86 (br s, 1H), 4.48-4.35 (m, 1H), 4.30-3.99 (m,4H), 3.95-3.73 (m, 1H), 3.60-3.39 (m, 2H). 3.29-2.94 (m, 5H), 2.93-2.67(m, 7H), 2.66-2.56 (m, 1H), 2.55-2.47 (m, 1H), 2.43 (d, J=4.6 Hz, 3H),2.35-2.13 (m, 2H), 1.36-1.25 (m, 1H), 1.09 (dd, J=3.0, 6.8 Hz, 3H).

Example 617

2-((S)-1-(2-fluoroacryloyl)-4-(7-(3-methylisoquinolin-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: benzyl(2S)-2-(cyanomethyl)-4-[7-(3-methyl-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.A mixture of benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate (300 mg, 593 μmol, 1.0 eq), 4-bromo-3-methyl-isoquinoline (198 mg,890 μmol, 1.5 eq), Cs₂CO₃ (483 mg, 1.48 mmol, 2.5 eq), BINAP-Pd-G3 (118mg, 119 μmol, 0.2 eq) in dioxane (6 mL) was degassed and purged with N₂3 times. The mixture was heated at 110° C. for 12 hours. The reactionmixture was diluted with water (20 mL) and extracted with ethyl acetate(3×30 mL). The combined organic layers were washed with brine (20 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive a residue. The residue was purified by column chromatography (SiO₂,Ethyl acetate/Methanol=100/1 to 10.1). benzyl(2S)-2-(cyanomethyl)-4-[7-(3-methyl-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 303 μmol, 51% yield, 98% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 647.

Step B:2-[(2S)-4-[7-(3-methyl-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[7-(3-methyl-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(50 mg, 77.3 μmol, 1.0 eq) in methanol (2 mL) was added dry Pd/C (10 mg,10% purity) and NH₃/MeOH (1 mL, 20% purity) under N₂. The suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred under H₂ (15 psi) at 25° C. for 0.5 hour. The mixture wasconcentrated under vacuum. The residue was purified by prep-HPLC(column: Waters Xbridge 150*25 5 u; mobile phase: [water (0.05% ammoniahydroxide v/v)-ACN]; B %: 30%-60%, 10 min). The desired fraction wascollected and lyophilized.2-[(2S)-4-[7-(3-methyl-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(7.81 mg, 14.9 μmol, 19% yield, 98.3% purity) was obtained as a yellowsolid. LCMS [ESI, M+1]: 513.

¹H NMR (400 MHz, chloroform-d) δ=9.07 (s, 1H), 8.14 (d, J=18.4 Hz, 1H),7.97 (d, J=8.0 Hz, 1H), 7.65 (dt, J=1.2, 7.6 Hz, 1H), 7.58-7.47 (m, 1H),4.41 (br dd, J=4.8, 10.4 Hz, 1H), 4.3 (s, 2H), 4.16 (dd, J=6.8, 10.8 Hz,1H), 4.10-3.93 (m, 1H), 3.91-3.77 (m, 1H), 3.57-3.37 (m, 2H), 3.36-3.21(m, 1H), 3.18-2.85 (m, 6H), 2.75-2.61 (m, 5H), 2.56 (br d, J=6.8 Hz,2H), 2.48 (s, 3H), 2.33-2.22 (m, 1H), 2.12-1.98 (m, 1H), 1.94-1.80 (m,3H).

Step C:2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[7-(3-methyl-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(3-methyl-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(80 mg, 156 μmol, 1.0 eq) and 2-fluoroprop-2-enoic acid (28.1 mg, 312μmol, 2.0 eq) in DMF (2 mL) was added T3P (297 mg, 468 μmol, 278 μL, 50%purity in ethyl acetate, 3.0 eq) and TEA (126 mg, 1.25 mmol, 173 μL, 8.0eq) at 0° C. The mixture was stirred at 0° C. for 0.5 hour. The reactionmixture was diluted with ethyl acetate (20 mL) and washed with water(3×20 mL). The combined organic layers were washed with brine (20 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive a residue. The residue was purified by column chromatography (SiO₂,Ethyl acetate/Methanol=100/1 to 10/1) and further purification byprep-HPLC (column: Waters Xbridge 150*25 5 u; mobile phase: [water(0.05% ammonia hydroxide v/v)-ACN]; B %: 35%-65%0, 10 min). The desiredfraction was collected and lyophilized.2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[7-(3-methyl-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(12 mg, 19.9 μmol, 13% yield, 97.4% purity, 100% ee) was obtained as ayellow solid. LCMS [ESI, M+1]: 585.

¹H NMR (400 MHz, chloroform-d) δ=9.08 (s, 1H), 8.26-8.04 (m, 1H), 7.97(br d, J=7.6 Hz, 1H), 7.73-7.60 (m, 1H), 7.58-7.49 (m, 1H), 5.42 (d,J=47.6 Hz, 1H), 5.27 (dd, J=3.6, 16.8 Hz, 1H), 4.85 (br s, 1H),4.45-3.92 (m, 7H), 3.83-3.25 (m, 4H), 3.22-2.59 (m, 10H), 2.49 (s, 3H),2.36-2.24 (m, 1H), 2.13-1.99 (m, 1H), 1.92-1.76 (m, 3H).

Example 618

(S)-benzyl-2-(cyanomethyl)-4-(7-(7-fluoroisoquinolin-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

Step A:(S)-benzyl-2-(cyanomethyl)-4-(7-(7-fluoroisoquinolin-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate.To a solution of benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(300 mg, 0.59 mmol, 1.0 eq) in toluene (10.0 mL) was added4-bromo-7-fluoro-isoquinoline (268 mg, 1.19 mmol, 2.0 eq), RuPhos (111mg, 237 μmol, 0.40 eq), Cs₂CO₃ (483 mg, 1.48 mmol, 2.5 eq) and Pd₂(dba)₃(109 mg, 118 μmol, 0.20 eq) at 25° C., the mixture was stirred at 90° C.for 16 hours. The reaction mixture was diluted with water (5.0 mL) andextracted with ethyl acetate (3×5.0 mL). The combined organic layerswere washed with brine (3×5.0 mL), dried over Na₂SO₄, filtered and thefiltrate was concentrated under reduced pressure to give a residue. Theresidue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=1/1 to Petroleum ether/Ethyl acetate/EtOH (2% N₃H₂O)4/3/1). Then the crude product was purified by reversed-phase HPLC (0.1%FA condition). The desired fractions were collected and concentratedunder vacuum to give(S)-benzyl-2-(cyanomethyl)-4-(7-(7-fluoroisoquinolin-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(105 mg, 160 μmol, 27% yield, 99% purity) as a yellow solid. LCMS [M+1]:651.

¹H NMR (400 MHz, chloroform-d) δ=2.04-2.08 (m, 4H), 2.69 (d, J=5.64 Hz,1H), 2.73 (d, J=5.52 Hz, 1H), 2.81-2.85 (m, 3H), 2.87-3.02 (m, 3H),3.09-3.19 (m, 1H), 3.32-3.45 (m, 3H), 3.45-3.55 (m, 1H), 3.57-3.68 (m,1H), 3.99 (br d, J=12.52 Hz, 1H), 4.09-4.17 (m, 1H), 4.28-4.34 (m, 1H),4.31 (m, 1H), 4.46 (dd, J=11.84, 4.31 Hz, 1H), 4.63-4.74 (m, 1H), 4.80(br dd, J=11.32, 6.82 Hz, 1H), 5.20-5.23 (m, 2H), 5.30-5.32 (m, 2H),7.35-7.42 (m, 5H), 7.47-7.53 (m, 1H), 7.60 (dd, J=8.68, 2.56 Hz, 1H),8.16 (dd, J=9.24, 5.25 Hz, 1H), 8.22-8.25 (m, 1H), 8.95-9.00 (m, 1H).

Step B:2-((S)-4-(7-(7-fluoroisoquinolin-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.To a solution of (S)-benzyl2-(cyanomethyl)-4-(7-(7-fluoroisoquinolin-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(30.0 mg, 46.1 μmol, 1.0 eq) in MeOH (1.0 mL) was added NH₃/MeOH (46.1μmol, 1.5 mL, 15% purity, 1.0 eq) and Pd/C (20.0 mg, 46.1 μmol, 10%purity, 1.0 eq) under N₂. The suspension was degassed under vacuum andpurged with H₂ (93.1 ug, 46.1 μmol, 1.0 eq) several times. The mixturewas stirred under H₂ (15 psi) at 25° C. for 1 hour. The reaction mixturewas filtered through a celite and washed with MeOH (20 mL). The filtratewas concentrated under reduced pressure at 45° C. to give a residue. Theresidue was purified by prep-HPLC (basic condition) (column: Xtimate C18150*25 mm*5 um; mobile phase. [water (0.05% ammonia hydroxide v/v)-ACN];B %: 43%-73%, 10 min). The desired fraction was collected andlyophilized.2-((S)-4-(7-(7-fluoroisoquinolin-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(7 mg, 13.3 μmol, 28.8% yield, 98% purity) was obtained as a yellowsolid. LCMS [M+1]: 517.

¹H NMR (400 MHz, chloroform-d) δ=1.75-1.90 (m, 3H), 1.99-2.13 (m, 1H),2.24-2.34 (m, 1H), 2.45-2.51 (m, 3H), 2.53-2.58 (m, 2H), 2.64-2.74 (m,1H), 2.80-2.88 (m, 2H), 2.89-2.96 (m, 1H), 2.97-3.06 (m, 1H), 3.07-3.18(m, 3H), 3.22-3.33 (m, 1H), 3.38-3.48 (m, 2H), 3.82-3.89 (m, 1H), 4.03(br d, J=12.36 Hz, 1H), 4.18 (dd, J=10.56, 6.69 Hz, 1H), 4.30 (s, 2H),4.40 (dd, J=10.64, 4.75 Hz, 1H), 7.49 (ddd, J=9.16, 8.35, 2.63 Hz, 1H),7.60 (dd, J=8.76, 2.50 Hz, 1H), 8.17 (dd, J=9.24, 5.38 Hz, 1H), 8.24 (s,1H), 8.96 (s, 1H).

Step C:2-[(2S)-4-[7-(7-fluoro-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.To a solution of2-[(2S)-4-[7-(7-fluoro-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(90.7 mg, 175 μmol, 1.0 eq) and 2-fluoroprop-2-enoic acid (31.6 mg, 351μmol, 2.0 eq) in DMF (2 mL) was added T3P (335 mg, 526 μmol, 313 μL, 50%purity in ethyl acetate. 3.0 eq) and TEA (142 mg, 1.40 mmol, 195 μL, 8.0eq) at 0° C. The mixture was stirred at 0° C. for 0.5 hour. The reactionmixture was diluted with ethyl acetate (20 mL) and washed with water(3×20 mL). The combined organic layers were washed with brine (20 mL),dried over Na₂SO₄, filtered and the filtrate was concentrated underreduced pressure to give a residue. The residue was purified by columnchromatography (SiO₂, Ethyl acetate/Methanol=100/1 to 10/1) and furtherpurification by prep-HPLC (column: Waters Xbridge 150*25 mm*5 um; mobilephase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 32%-59%, 10 min).The desired fraction was collected and lyophilized2-[(2S)-4-[7-(7-fluoro-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile(8 mg, 13.4 μmol, 7.6% yield, 98.3% purity, 100% ee) was obtained as awhite solid LCMS [M+1]: 589.

¹H NMR (400 MHz, chloroform-d) δ=8.97 (s, 1H), 8.24 (s, 1H), 8.16 (dd,J=5.2, 9.2 Hz, 1H), 7.60 (dd, J=2.4, 8.8 Hz, 1H), 7.54-7.40 (m, 1H),5.55-5.33 (m, 1H), 5.27 (dd, J=3.6, 16.8 Hz, 1H), 4.87 (br s, 1H),4.44-3.94 (m, 7H), 3.72-3.28 (m, 4H), 3.22-3.06 (m, 2H), 3.04-2.93 (m,2H), 2.93-2.74 (m, 2H), 2.72-2.66 (m, 1H), 2.49 (s, 3H), 2.36-2.24 (m,1H), 2.13-2.03 (m, 1H), 1.92-1.76 (m, 3H).

Example 619

2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[7-(5-methyl-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-51H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

Step A: benzyl(2S)-4-[7-(1-chloro-5-methyl-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.Benzyl (23)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(300 mg, 593 μmol, 1.0 eq), 4-bromo-1-chloro-5-methyl-isoquinoline (198mg, 771 μmol, 1.3 eq), Pd₂(dba)₃ (109 mg, 119 μmol, 0.2 eq) and Cs₂CO₃(483 mg, 1.48 mmol, 2.5 eq), XantPhos (137 mg, 237 μmol, 0.4 eq) intoluene (10 mL) was de-gassed and then heated to 95° C. for 10 hoursunder N₂. Upon completion, the mixture was filtered and the filtrate wasconcentrated under vacuum. The residue was purified by chromatography(Al₂O₃, petroleum ether/ethyl acetate 2/1 to 0/1) followed by reversedphase flash [water (0.1% FA)/acetonitrile]. The desired fractions werecollected and neutralized with solid NaHCO₃, concentrated under vacuumto remove MeCN and extracted with ethyl acetate (2×15 mL). The organiclayers were dried over Na₂SO₄ and concentrated under vacuum to givebenzyl(2S)-4-[7-(1-chloro-5-methyl-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5f-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(150 mg, 209 μmol, 35% yield, 95% purity) as a yellow solid. LCMS [ESI,M+1]: 681.

1H NMR (400 MHz, chloroform-d) δ 8.27 (d, J=8.0 Hz, 1H), 8.08-7.99 (m,1H), 7.60-7.51 (m, 2H), 7.44-7.36 (m, 5H), 5.25-5.17 (m, 2H), 4.74-4.60(m, 1H), 4.41-4.32 (m, 1H) 4.28-4.14 (m, 2H), 4.08-3.88 (m, 2H), 3.83(br d, J=17.6 Hz, 1H), 3.61-3.51 (m, 1H), 3.50-3.36 (m, 1H), 3.31-2.94(m, 6H), 2.91 (d, J=2.4 Hz, 3H), 2.81-2.59 (m, 4H). 2.46 (d, J=4.0 Hz,3H), 2.33-2.21 (m, 1H), 2.06-1.97 (m, 1H), 1.92-1.72 (m, 3H).

Step B:2-[(2S)-4-[7-(1-chloro-5-methyl-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of benzyl(2S)-4-[7-(1-chloro-5-methyl-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(130 mg, 191 μmol, 1 eq) in MeOH (3 mL) was added NH₃·MeOH (2 mL, 20%purity), Pd/C (65 mg, 10% purity) under N₂. The suspension was degassedunder vacuum and purged with H₂ several times. The mixture was stirredat 25° C. for 2 hours. Upon completion, the catalyst was removed byfiltering through a plug of celite. The solvent was removed underreduced pressure to give 80 mg of crude product. Taking 20 mg of thecrude product was purified by prep-HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN); B %:28%-58%, 10 min). The desired fractions were collected and lyophilizedto give2-[(2S)-4-[7-(5-methyl-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido(3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(10.8 mg, 21.0 μmol, 44% yield, 99.9% purity) as a yellow solid. LCMS[ESI, M+1]: 513.

Step C:2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[7-(5-methyl-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of 2-fluoroprop-2-enoic acid (24.6 mg, 273 μmol, 2.0 eq)and DIEA (70.6 mg, 546 μmol, 95.1 μL, 4.0 eq) in DCM (1.4 mL) was addedHATU (77.9 mg, 205 μmol, 1.5 eq) at 0° C. After stirring at 0° C. for 20minutes,2-[(2S)-4-[7-(5-methyl-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(70 mg, 137 μmol, 1.0 eq) was added into the mixture. The mixture wasstirred at 25° C. for 40 minutes. Upon completion, the mixture wasdiluted with water (2 mL) and extracted with dichloromethane (6×5 mL).The organic layers were dried over Na₂SO₄ and concentrated under vacuum.The residue was purified by chromatography (Al₂O₃, petroleum ether/ethylacetate 1/1 to ethyl acetate/methanol 10/1) followed by prep-HPLC(column: Waters Xbridge 150*25 5 u; mobile phase: [water (0.05% ammoniahydroxide v/v)-ACN]; B %: 35%-65%, 10 min). The desired fractions werecollected and lyophilized to give2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[7-(5-methyl-4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(20.6 mg, 34.3 μmol, 25% yield, 97.3% purity) as a white solid. LCMS[ESI, M+1]: 585.

¹H NMR (400 MHz, chloroform-d) δ=9.03 (d, J=6.0 Hz, 1H), 8.30 (d, J=16.8Hz, 1H), 7.83 (br d, J=7.6 Hz, 1H), 7.55-7.44 (m, 2H), 5.54-5.32 (m,1H), 5.31-5.18 (m, 1H), 5.09-4.48 (m, 1H), 4.43-4.34 (m, 1H), 4.32-4.07(m, 4H), 4.06-3.81 (m, 2H), 3.64-3.42 (m, 2H) 3.35-3.26 (m, 1H),3.25-2.96 (m, 4H), 2.92 (d, J=2.8 Hz, 3H), 2.90-2.73 (m, 2H), 2.72-2.61(m, 2H), 2.51-2.42 (m, 3H), 2.34-2.23 (m, 1H), 2.13-1.99 (m, 1H),1.92-1.73 (m, 3H).

Example 620

1-[4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-6-fluoro-1,4-diazepan-1-yl]-2-fluoro-prop-2-en-1-one

Step A: tert-butyl 4-benzyl-6-fluoro-1,4-diazepane-1-carboxylate.tert-butyl 4-benzyl-6-fluoro-1,4-diazepane-1-carboxylate. To a solutionof tert-butyl (3R)-4-benzyl-3-(hydroxymethyl) piperazine-1-carboxylate(1.5 g, 4.90 mmol, 1 eq) in DCM (40 mL) was added DAST (3.95 g, 24.48mmol, 3.23 mL, 5 eq) drop-wise at 0° C., and the mixture was stirred at20° C. for 5 hrs. The mixture was added sat, NaHCO₃ (30 mL) andextracted with ethyl acetate (30 mL×2). The organic layer was dried overNa₂SO₄, filtered, concentrated. The residue was purified by silica gelcolumn chromatography (PE:EA=20˜5:1) to give tert-butyl4-benzyl-6-fluoro-1,4-diazepane-1-carboxylate (980 mg, 3.18 mmol, 64.91%yield) as yellow oil. LCMS [ESI, M+1]: 309.

Step B: tert-butyl 6-fluoro-1, 4-diazepane-1-carboxylate. To a solutionof tert-butyl 4-benzyl-6-fluoro-1,4-diazepane-1-carboxylate (900.00 mg,2.92 mmol, 1 eq) and Pd/C (200 mg, 2.92 mmol, 10% purity, 1 eq) andPd(OH)₂ (179.92 mg, 1.28 mmol, 4.39 e-1 eq) in MeOH (20 mL) and themixture was stirred at 40° C. for 12 hrs under H₂ (50 psi). The mixturewas filtered, concentrated to give tert-butyl 6-fluoro-1,4-diazepane-1-carboxylate (630 mg, 2.89 mmol, 98.90% yield) as colorlessoil.

Step C:[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]trifluoromethanesulfonate. To a solution of7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-ol(700 mg, 1.65 mmol, 1 eq) and TEA (500.09 mg, 4.94 mmol, 687.88 μL, 3eq), 4A molecular sieves (500 mg) in DCM (7 mL) was added Tf₂O (697.18mg, 2.47 mmol, 407.71 μL, 1.5 eq) at −40° C., and stirred at 0° C. for30 min. The mixture was added water (2 mL) and extracted with DCM (5mL). The organic layer was dried over Na₂SO₄, filtered, concentrated.The residue was purified by silica gel column chromatography(PE:EA=10˜1:1) to give[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]trifluoromethanesulfonate (470 mg, 843.83 μmol, 51.22% yield) as redoil. LCMS [ESI, M+1]: 557.

Step D: tert-butyl4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-6-fluoro-1,4-diazepane-1-carboxylate.To solution of[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d] pyrimidin-4-yl],trifluoromethanesulfonate (440 mg, 789.97 μmol, 1 eq) andtert-butyl-6-fluoro-1, 4-diazepane-1-carboxylate (258.64 mg, 1.18 mmol,1.5 eq) in DMAC (5 mL) was added DIEA (306.29 mg, 2.37 mmol, 412.79 μL,3 eq), and the mixture was stirred at 25° C. for 30 min. The mixture waspurified by reverse silica gel column chromatography column (0.001 FA)to give tert-butyl4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-6-fluoro-1,4-diazepane-1-carboxylate(260 mg, 415.88 μmol, 52.65% yield) as yellow solid. LCMS [ESI, M+1]:625.

Step E:7-(8-chloro-1-naphthyl)-4-(6-fluoro-1,4-diazepan-1-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine.To a solution of tert-butyl4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-6-fluoro-1,4-diazepane-1-carboxylate(240.00 mg, 383.89 μmol, 1 eq) in DCM (3 mL) was added TFA (12.32 g,108.05 mmol, 8.00 mL, 281.45 eq), and the mixture was stirred at 20° C.for 30 min. The mixture was concentrated, and added DCM (10 mL), washedwith sat·Na₂CO₃ (5 mL). The organic layer was dried over Na₂SO₃,filtered, concentrated to give7-(8-chloro-1-naphthyl)-4-(6-fluoro-1,4-diazepan-1-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (200 mg, crude) as yellow solid. Some of this material (160mg, 304.73 μmol) was used directly in the next step. 40 mg of crudeproduct was purified by prep-HPLC (purified by prep-HPLC (column:Shim-pack C18 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B %:4%-34%, 10 min), then residue was prep-HPLC (column: Xtimate C18 150*25mm*5 um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %:60%-90%, 10 min) to give7-(8-chloro-1-naphthyl)-4-(6-fluoro-1,4-diazepan-1-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(9 mg, 16.99 μmol). LCMS [ESI, M+1]: 523.

¹H NMR (400 MHz, chloroform-d) δ=7.76 (d, J=8.07 Hz, 1H) 7.61 (t, J=8.38Hz, 1H) 7.52 (br d, J=7.46 Hz, 1H) 7.44 (dt, J=15.86, 7.90 Hz, 1H) 7.34(t, J=7.76 Hz, 1H) 7.25-7.18 (dd, J=7.46 Hz, 1H) 4.80-5.24 (m, 1H)4.31-4.46 (m, 2H) 4.08-4.30 (m, 2H) 3.71-4.04 (m, 3H) 3.50-3.68 (m, 2H)2.81-3.37 (m, 7H) 2.46-2.73 (m, 5H) 2.25-2.35 (m, 1H) 2.01-2.14 (m, 1H)1.82-1.91 (m, 3H).

Step F: 1-[4-[7-(8-chloro-1-naphthyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-6-fluoro-1,4-diazepan-1-yl]-2-fluoro-prop-2-en-1-one.To a solution of7-(8-chloro-1-naphthyl)-4-(6-fluoro-1,4-diazepan-1-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (150.00 mg, 285.68 μmol, 1 eq) and 2-fluoroprop-2-enoic acid(51.45 mg, 571.36 μmol, 2 eq) in EA (2 mL) was added T3P (50 M, 17.14μL, 3 eq) and TEA (231.27 mg, 2.29 mmol, 318.11 μL, 8 eq) at −40° C.,and the mixture was stirred at −40° C. for 30 min. The mixture wasdiluted with water (2 mL) and extracted with ethyl acetate (2 mL×2). Theorganic layer was dried over Na₂SO₄, filtered, concentrated. The residuewas purified by prep-HPLC (column: Shim-pack C18 150*25*10 um; mobilephase: [water (0.225% FA)-ACN]; B %: 18%-48%, 10 min) to give1-[4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-6-fluoro-1,4-diazepan-1-yl]-2-fluoro-prop-2-en-1-one(90 mg, 140.78 μmol, 49.28% yield, 93.4% purity) as yellow solid. LCMS[ESI, M+1]: 597.

¹H NMR (400 MHz, chloroform-d) δ=7.76 (d, J=8.19 Hz, 1H) 7.58-7.66 (m,1H) 7.50-7.56 (m, 1H) 7.38-7.50 (m, 1H) 7.31-7.37 (m, 1H) 7.24-7.16 (m,1H) 4.90-5.55 (m, 3H) 4.32-4.48 (m, 2H) 3.48-4.27 (m, 1H) 3.21-3.43 (m,1H) 2.80-3.16 (m, 2H) 2.44-2.73 (m, 5H) 2.25-2.36 (m, 1H) 2.00-2.14 (m,1H) 1.77-1.91 (m, 3H).

Example 621

1-[(3R)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-(difluoromethyl)piperazin-1-yl]-2-fluoro-prop-2-en-1-one

Step A: tert-butyl(3R)-4-benzyl-3-(hydroxymethyl)piperazine-1-carboxylate. A reactionmixture of tert-butyl (3R)-3-(hydroxymethyl)piperazine-1-carboxylate (10g, 46.2 mmol, 1 eq), BnBr (8.70 g, 50.9 mmol, 6.04 mL, 1.1 eq) and TEA(7.02 g, 69.36 mmol, 9.65 mL, 1.5 eq) in MeCN (100 mL) was heated to 80°C. for 12 hours. Upon completion, the reaction mixture was concentratedunder vacuum. The residue was dissolved into water (30 mL) and ethylacetate (50 mL). The mixture was extracted with ethyl acetate (3×50 mL).The combined organic layers were washed with brine (30 mL), dried overNa₂SO₄, and concentrated under vacuum. The residue was purified bysilica gel chromatography (petroleum ether:ethyl acetate=5:1 to 3:1).tert-butyl (3R)-4-benzyl-3-(hydroxymethyl)piperazine-1-carboxylate (9 g,29.4 mmol, 64% yield, 100% purity) was obtained as a white solid. LCMS[ESI, M+1]: 307.

¹H NMR (400 MHz, chloroform-d) δ=7.28-7.20 (m, 5H), 3.95 (br d, J=13.2Hz, 1H), 3.79 (dd, J=5.6, 11.6 Hz, 1H), 3.61 (br dd, J=3.2, 13.6 Hz,1H), 3.52 (br dd, J=4.0, 11.2 Hz, 2H), 3.35 (br d, J=13.3 Hz, 2H), 3.09(br s, 1H), 2.77-2.65 (m, 1H), 2.51 (br s, 1H), 2.20 (ddd, J=3.2, 8.4,12.0 Hz, 1H), 1.38 (s, 9H).

Step B: tert-butyl (3R)-4-benzyl-3-formyl-piperazine-1-carboxylate. DMSO(13.8 g, 176 mmol, 13.8 mL, 6.0 eq) was added to a to −65° C. solutionof (COCl)₂ (11.2 g, 88.1 mmol, 7.71 mL, 3.0 eq) in dichloromethane (90mL). After 10 min, a solution of tert-butyl(3R)-4-benzyl-3-(hydroxymethyl)piperazine-1-carboxylate (9 g, 29.4 mmol,1 eq) in dichloromethane (40 mL) was slowly introduced over 15 minutes.After stirring at −65° C. for 1 hour, TEA (29.7 g, 294 mmol, 40.9 mL,10.0 eq) was added. The mixture was warmed to 28° C. over 30 min andthen stirred for another 30 min at that temperature. Upon completion,the reaction mixture was quenched with water (5 mL) and separated. Theorganic layer was dried over Na₂SO₄ and concentrated under vacuumtert-butyl (3R)-4-benzyl-3-formyl-piperazine-1-carboxylate (8.9 g, 29mmol) was obtained as a yellow oil which was used for next step withoutfurther purification.

Step C: tert-butyl(3R)-4-benzyl-3-(difluoromethyl)piperazine-1-carboxylate. To a solutionof tert-butyl (3R)-4-benzyl-3-formyl-piperazine-1-carboxylate (8.9 g,29.2 mmol, 1.0 eq) in dichloromethane (180 mL) was added DAST (9.43 g,58.5 mmol, 7.73 mL, 2 eq) at 0° C. The reaction mixture was stirred at0° C. for 2 hours. Upon completion, the reaction mixture was quenched bysaturated NaHCO₃ (150 mL) and extracted with ethyl acetate (3×150 mL).The combined organic layers were washed with brine (60 mL) andconcentrated under vacuum. The residue (Petroleum ether:Ethylacetate=5:1) was purified by silica gel chromatography (Petroleumether:Ethyl acetate=1:0 to 10:1). tert-butyl(3R)-4-benzyl-3-(difluoromethyl)piperazine-1-carboxylate (1.5 g, 4.48mmol, two steps 15% yield, 97.5% purity) was obtained as a yellow oil.LCMS [ESI, M+1]: 327.

Step D: tert-butyl (3R)-3-(difluoromethyl)piperazine-1-carboxylate. To asolution of tert-butyl(3R)-4-benzyl-3-(difluoromethyl)piperazine-1-carboxylate (1.5 g, 4.60mmol, 1.0 eq) in MeOH (10 mL) was added Pd/C (150 mg, 10% purity),Pd(OH)₂/C (150 mg, 20% purity) under N₂. The suspension was degassedunder vacuum and purged with H₂ several times. The mixture was stirredunder H₂ (50 psi) at 40° C. for 12 hours. Upon completion, the mixturewas filtered and the filtrate was concentrated under vacuum. tert-butyl(3R)-3-(difluoromethyl)piperazine-1-carboxylate (1.0 g, 4.23 mmol, 92%yield) was obtained as a yellow oil which was used for next step withoutfurther purification.

1H NMR (400 MHz, chloroform-d) δ=5.91-5.43 (m, 1H), 4.17-3.78 (m, 2H),3.13-2.66 (m, 5H), 1.48 (s, 9H).

Step E:[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]trifluoromethanesulfonate. To a solution of7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-ol(1.0 g, 2.35 mmol, 1 eq), 4A molecular sieve (1.0 g) and TEA (953 mg,9.41 mmol, 1.31 mL, 4.0 eq) in dichloromethane (20 mL) was added Tf₂O(996 mg, 3.53 mmol, 582 uL, 1.5 eq) at −40° C. and stirred for 0.5hours. Upon completion, the reaction mixture was quenched by water (15mL). The mixture was filtered through a pad of celite. The filtrateseparated and the aqueous layers were extracted with dichloromethane (30mL). The organic layers were washed with brine (10 mL), dried overNa₂SO₄ and concentrated under vacuum. The mixture was purified by silicagel chromatography (SiO₂, Petroleum ether:Ethyl acetate=5.1 to 0:1) togive[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]trifluoromethanesulfonate (1.0 g, 1.63 mmol, 69% yield, 91% purity) as abrown oil. LCMS [ESI, M+1]: 557.

Step F: tert-butyl(3R)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-(difluoromethyl)piperazine-1-carboxylate.A reaction mixture of[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]trifluoromethanesulfonate (1.0 g, 1.80 mmol, 1.0 eq) and tert-butyl(3R)-3-(difluoromethyl)piperazine-1-carboxylate (780 mg, 3.30 mmol, 1.84eq) was stirred at 90° C. for 5 hours. Upon completion, the reactionmixture was dissolved in MeCN (5 mL). The reaction mixture was purifiedby reversed-phase flash [water (0.1% FA)/acetonitrile]. The fractionswere basidified by solid NaHCO₃ to pH>7 and concentrated under vacuum.The aqueous layer was extracted with Ethyl acetate (3×20 mL) andconcentrated under vacuum. The residue was purified by prep-TLC(dichloromethane:MeOH=7:1) to give tert-butyl(3R)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-(difluoromethyl)piperazine-1-carboxylate(80 mg, 122 μmol, 7% yield, 98% purity) as a brown oil. LCMS [ESI, M+1]:643.

Step G:7-(8-chloro-1-naphthyl-4-[2R)-2-difluoromethyl)piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine.To a solution of tert-butyl(3R)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-(difluoromethyl)piperazine-1-carboxylate(20 mg, 31.1 μmol, 1 eq) in dichloromethane (0.05 mL) was added TFA(70.9 mg, 622 μmol, 46.0 μL, 20 eq). The reaction mixture was stirred at25° C. for 1 hour. Upon completion, the reaction mixture was quenched bysaturated Na₂CO₃ (4 mL) and extracted with dichloromethane: MeOH (10:1,3×8 mL). The combined organic layers were dried over Na₂SO₄ andconcentrated under vacuum. The residue was purified by Prep-HPLC(column: Waters Xbridge 150*25 5 u; mobile phase: [water (10 mMNH4HCO3)-ACN]; B %: 43%-73%, 10 min). The fractions were concentratedand lyophilized.7-(8-chloro-1-naphthyl)-4-[(2R)-2-(difluoromethyl)piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(4.22 mg, 7.77 μmol, 25% yield, 100% purity) was obtained as a whitesolid. LCMS [ESI, M+1]: 543.

1H NMR (400 MHz, chloroform-d) δ=7.81-7.74 (m, 1H), 7.66-7.59 (m, 1H),7.56-7.52 (m, 1H), 7.50-7.40 (m, 1H), 7.35 (t, J=7.6 Hz, 1H), 7.28-7.16(m, 1H), 6.69-6.09 (m, 1H), 4.68-4.54 (m, 1H), 4.51-4.34 (m, 2H),4.30-4.11 (m, 1H), 4.07-3.68 (m, 2H), 3.63-3.46 (m, 2H), 3.44-3.31 (m,2H), 3.30-3.21 (m, 1H), 3.20-2.97 (m, 4H), 2.92-2.83 (m, 1H), 2.78-2.67(m, 1H), 2.58-2.49 (m, 3H), 2.38-2.26 (m, 1H), 2.15-2.02 (m, 1H),1.94-1.73 (m, 3H).

Step H:1-[(3R)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido3,4-d]pyrimidin-4-yl-3-(difluoromethyl)piperazin-1-yl-2-fluoro-prop-2-en-1-one.To a solution of7-(8-chloro-1-naphthyl)-4-[(2R)-2-(difluoromethyl)piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(45 mg, 82.9 μmol, 1.0 eq), 2-fluoroprop-2-enoic acid (22.4 mg, 249μmol, 3.0 eq) in Ethyl acetate (1 mL) was added 4A molecular sieve (100mg). After stirring at 25° C. for 0.5 hour, TEA (126 mg, 1.24 mmol, 173μL, 15 eq) and T3P (211 mg, 331 μmol, 197 μL, 50% purity, 4 eq) wasadded at 0° C. The mixture was stirred at 25° C. for 0.5 hour. Uponcompletion, the reaction mixture was quenched by water (1 mL) andextracted with Ethyl acetate (3×5 mL). The combined organic layers weredried over Na₂SO₄ and concentrated under vacuum. The residue waspurified by column (Al₂O₃, Petroleum ether:Ethyl acetate=3:1 to 0:1),followed by prep-HPLC (column: Waters Xbridge 150*25 5 u; mobile phase:[water (0.05% ammonia hydroxide v/v)-ACN]; B %: 55%-85%, 10 min) to give1-[(3R)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-(difluoromethyl)piperazin-1-yl]-2-fluoro-prop-2-en-1-one(5.98 mg, 9.72 μmol, 11% yield, 99.4% purity) as a white solid. LCMS[ESI, M+1]: 615.

1H NMR (400 MHz, chloroform-d) δ=7.81-7.75 (m, 1H), 7.67-7.61 (m, 1H),7.55 (td, J=1.2, 7.6 Hz, 1H), 7.51-7.41 (m, 1H), 7.36 (t, J=7.6 Hz, 1H),7.28-7.17 (m, 1H), 6.48-5.83 (m, 1H), 5.47-5.31 (m, 1H), 5.27-5.19 (m,1H), 4.88-4.65 (m, 1H), 4.59-4.31 (m, 4H), 4.21-4.10 (m, 1H), 4.04-3.76(m, 2H), 3.69-3.44 (m, 3H), 3.33-2.92 (m, 4H), 2.75-2.64 (m, 1H),2.61-2.52 (m, 1H), 2.49-2.48 (m, 3H), 2.36-2.25 (m, 1H), 2.13-2.02 (m,1H), 1.88-1.72 (m, 3H).

EXAMPLES 622-678 listed in Table 1 are prepared using commerciallyavailable intermediates and/or those intermediates disclosed hereinfollowing the methods outlined in the general reactions schemes and theteachings of the exemplified Examples.

TABLE 1 EXAMPLES 622-678 Example No. Structure 622

623

624

625

626

627

628

629

630

631

632

633

634

635

636

637

638

639

640

641

642

643

644

645

646

647

648

649

650

651

652

653

654

655

656

657

658

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661

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664

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678

Example A KRas G12C Modification Assay

This Example illustrates that exemplary compounds of the presentinvention covalently bind to KRas G12C using a LCMS assay to detect acovalent adduct of the exemplary compound and KRAS G12C.

The protein concentration of GDP-loaded K-Ras (1-169) G12C,C51S,C80L,C118S and GTP-loaded K-Ras (1-169) G12C,C51S,C80L,C118S,Q61Hwas adjusted to 2 μM in K-Ras Assay Buffer (25 mM HEPES, 150 mM NaCl, 5mM MgCl₂, and 10 mM Octyl β-glucopyranoside at pH˜7.5). A 10 μL aliquotof each protein solution was then transferred to a 384 well microtiterplate. Initial compound stocks were generated at fifty times theirdesired final assay concentration in DMSO.

Exemplary compounds of Formula (I) were diluted 25-fold into K-Ras AssayBuffer to a final of two times their final concentration A 10 μL aliquotof each diluted compound solution was then added to each of the proteinsolutions in the microtiter plate to initiate reaction. Typical finalcompound concentrations were 3.0, 5.0 and 25.0 μM. At each time point,the reactions were quenched with 20 μL, of a 25 mM acetic acid solution.Usual assay endpoints were 15, 180 and 1440 minutes. Once all reactionswere quenched, the plates were heat sealed and the samples were injectedinto a LC/MS system for data acquisition.

Data collection took place on an Agilent 6520 Q-TOF Accurate MassSpectrometer. Samples were injected in their liquid phase onto a C-3reverse phase column to remove assay buffer and prepare the samples formass spectrometer. The proteins were eluted from the column using anacetonitrile gradient and fed directly into the mass analyzer. Initialraw data analysis took place in Agilent MassHunter software immediatelypost data acquisition.

Raw data analysis of the intact protein was exclusively a deconvolutionof the multiple charge states of each protein in solution using amaximum entropy deconvolution provided in Mass Hunter. To minimizecomplexity, only the data over limited mass ranges were considered foranalysis, with a minimum of one Dalton mass step intervals. The heightsof all masses identified during raw data analysis were exported to befurther analyzed in Spotfire® data analysis software.

Final data analysis was a multistep process in the Spotfire® dataanalysis software package. Briefly, each protein mass was calculated asa percent of the total signal of that sample, that percentage was thennormalized to the percentage of signal of the protein in the absence ofreactive compounds. Those normalized signals were reported as normalizedpercent of control (POC). An increased POC value indicates a compoundthat displays a higher degree of modification at a given conditioncompared to other compounds under the same conditions. The results forexemplary compounds of Formula (I) and Formula (II) tested at 5 μMconcentration for 3 hours are shown in Table 2. Key: “A”≤25% POC;“B”>25% POC-≤50% POC; “C”>50% POC and ND=not determined.

TABLE 2 Inhibition of KRas G12C Activity by Exemplary Compounds ExampleNo. POC 1 B 2 A 3 A 4 A 5 A 6 B 7 A 8 B 9 C 10 C 11 C 12 C 13 C 14 C 15C 16 C 17 B 18 C 19 C 20 C 21 C 22 C 23 C 24 A 25 A 26 C 27 C 28 C 29 C30 A 31 B 32 C 33 B 34 A 35 C 36 C 37 C 38 C 39 C 40 C 41 A 42 A 43 C 44C 45 A 46 A 47 C 48 C 49 B 50 C 51 A 52 C 53 C 54 A 55 C 56 C 57 C 58 C59 C 60 C 61 C 62 C 63 C 64 C 65 C 66 C 67 C 68 A 69 A 70 C 71 A 72 C 73C 74 C 75 C 76 C 77 C 78 C 79 A 80 C 81 C 82 C 83 C 84 A 85 C 86 A 87 A88 C 89 C 90 C 91 A 92 C 93 C 94 A 95 A 96 A 97 C 98 C 99 C 100 C 101 C102 C 103 C 104 C 105 B 106 A 107 C 108 C 109 C 110 C 111 C 112 A 113 C114 B 115 C 116 C 117 C 118 A 119 B 120 C 121 C 122 C 123 A 124 C 125 A126 C 127 C 128 C 129 C 130 C 131 C 132 C 133 C 134 C 135 C 136 C 137 C138 C 139 C 140 C 141 C 142 C 143 C 144 C 145 C 146 B 147 C 148 C 149 B150 C 151 B 152 C 153 C 154 C 155 C 156 C 157 C 158 C 159 C 160 C 161 C162 B 163 C 164 C 165 C 166 B 167 B 168 C 169 C 170 C 171 C 172 C 173 C174 C 175 C 176 C 177 C 178 C 179 C 180 C 181 C 182 C 183 C 184 C 185 C186 B 187 C 188 C 189 C 190 C 191 C 192 C 193 C 194 C 195 C 196 C 197 C198 C 199 C 200 C 201 B 202 C 203 C 204 C 205 C 206 C 207 C 208 C 209 C210 C 211 C 212 C 213 C 214 C 215 C 216 C 217 C 218 C 219 C 220 C 221 C222 C 223 C 224 C 225 C 226 C 227 A 228 C 229 C 230 C 231 C 232 C 233 C234 C 235 C 236 C 237 C 238 C 239 C 240 C 241 C 242 C 243 C 244 C 245 C246 C 247 C 248 C 249 C 250 C 251 C 252 C 253 C 254 C 255 A 256 C 257 C258 C 259 C 260 C 261 A 262 A 263 C 264 C 265 C 266 C 267 C 268 C 269 C270 C 271 C 272 C 273 C 274 C 275 C 276 C 277 C 278 C 279 C 280 C 281 C282 A 283 C 284 C 285 C 286 C 287 C 288 A 289 C 290 C 291 C 292 A 293 C294 C 295 A 296 C 297 C 298 C 299 C 300 C 301 C 302 C 303 C 304 C 305 C306 C 307 C 308 C 309 C 310 C 311 C 312 C 313 C 314 C 315 C 316 C 317 C318 C 319 C 320 C 321 B 322 C 323 C 324 C 325 C 326 C 327 C 328 C 329 C330 C 331 C 332 C 333 C 334 C 335 C 336 C 337 C 338 C 339 C 340 C 341 C342 C 343 C 344 C 345 C 346 C 347 C 348 C 349 C 350 C 351 C 352 C 353 C354 C 355 A 356 C 357 A 358 C 359 C 360 C 361 C 362 C 363 C 364 C 365 C366 C 367 C 368 C 369 C 370 C 371 C 372 C 373 C 374 C 375 C 376 C 377 C378 C 379 C 380 C 381 C 382 C 383 C 384 C 385 C 386 C 387 C 388 C 389 C390 C 391 C 392 C 393 C 394 C 395 C 396 C 397 C 398 C 399 C 400 C 401 C402 C 403 C 404 C 405 C 406 C 407 C 408 C 409 C 410 C 411 C 412 C 413 C414 C 415 C 416 C 417 C 418 C 419 C 420 C 421 C 422 C 423 C 424 C 425 C426 C 427 C 428 C 429 C 430 C 431 C 432 C 433 C 434 C 435 C 436 C 437 C438 C 439 C 440 C 441 C 442 C 443 C 444 C 445 C 446 C 447 C 448 C 449 C450 C 451 C 452 C 453 C 454 C 455 C 456 C 457 C 458 C 459 C 460 C 461 C462 C 463 C 464 C 465 C 466 C 467 N.D. 468 N.D. 469 N.D. 470 N.D. 471 C472 C 473 C 474 C 475 C 476 C 477 C 478 C 479 C 480 C 481 C 482 C 483 C484 C 485 A 486 C 487 A 488 B 489 C 490 C 491 C 492 A 493 C 494 C 495 C496 C 497 C 498 C 499 C 500 C 501 C 502 C 503 C 504 C 505 C 506 C 507 C508 C 509 C 510 C 511 C 512 A 513 C 514 A 515 N.D. 516 N.D. 517 N.D. 518N.D. 519 N.D. 520 N.D. 521 N.D. 522 N.D. 523 N.D. 524 C 525 B 526 C 527N.D. 529 C 530 C 542 C 543 C 554 C 555 C 556 C 557 C 558 C 559 C 560 C561 C 562 C 563 C 564 C 565 C 566 C 567 C 568 C 569 N.D. 570 N.D. 571 C572 C 573 N.D. 574 C 575 C 576 C 577 C 578 C 579 C 580 C 581 C 582 C 583C 584 N.D. 585 C 586 C 587 A 588 C 589 C 590 B 591 B 592 C 593 C 594 A595 C 596 C 597 C 598 C 599 C 600 C

Example B Inhibition of KRas G12C-Dependent Cell Growth

This Example illustrates that exemplary compounds of the presentinvention inhibit the growth of tumor cell lines that express KRas G12C.

The cellular inhibition of KRAs G12C by exemplary compounds of thepresent invention was determined by measuring the amount of a downstreammarker of KRas activity, phosphorylated ERK (“Phospho-ERK”).

NCI-H358 cells (ATCC CRL-5807) express KRas G12C and were grown in RPMImedium supplemented with 10% fetal bovine serum, penicillin/streptomycinand 10 mM HEPES. Cells were plated in poly-D-Lysine coated 96-wellplates at a concentration of 50,000 cells/well and allowed to attach for8-12 hours. Diluted compounds were then added at a final concentrationof 0.5% DMSO. After 3 hours, the medium was removed, 150 μL of 4%formaldehyde was added and the plates were incubated for 20 minutes. Theplates were washed with PBS, and permeabilized using 150 μL of ice cold100% methanol for 10 minutes. Non-specific antibody binding to theplates was blocked using 100 μL Licor Blocking Buffer (Li-CorBiotechnology, Lincoln NE) for 1 hour at room temperature. Positivecontrol samples and samples lacking cells were parallel processed withtest samples as standards.

The amount Phospho-ERK was determined using an antibody specific for thephosphorylated form of ERK and compared to the amount of GAPDH. Primaryantibodies used for detection were added as follows: Phospho-ERK (CellSignaling cs9101) diluted 1:500 and GAPDH (Millipore MAB374) diluted1:5000 in Licor block+0.05% Tween 20. The plates were incubated for 21hours at room temperature. The plates were washed with PBS+0.05% Tween20.

Secondary antibodies used to visualize primary antibodies were added asfollows: Anti-rabbit-680 diluted 1:1000 and Anti-mouse-800 diluted1:1000 in Licor Block+0.05% Tween 20 and incubated for 1 hour at roomtemperature. The plates were washed with PBS+0.05% Tween 20. A 100 μLaliquot of PBS was added to each well and the plates were read on aLICOR AERIUS plate reader.

The pERK(Thr202/Tyr204) signal was normalized with the GAPDH signal andpercent of DMSO control values were calculated. IC₅₀ values weregenerated using a 4 parameter fit of the dose response curve. Theresults for exemplary compounds of Formula (I). Formula (II) are shownin Table 3. Key: “A”≥0.0001-≤1 μM; “B”>1 μM and ND=not determined.

TABLE 3 Inhibition of KRas G12C-mediated Cell Proliferation by ExemplaryCompounds Example No. IC₅₀ 1 B 2 B 3 B 4 B 5 B 6 B 7 B 8 B 9 B 10 B 11 A12 B 13 B 14 B 15 B 16 B 17 B 18 B 19 A 20 B 21 A 22 B 23 B 24 B 25 B 26B 27 A 28 A 29 B 30 B 31 B 32 A 33 B 34 B 35 B 36 B 37 B 38 A 39 A 40 A41 B 42 B 43 B 44 B 45 B 46 B 47 B 48 B 49 B 50 B 51 B 52 A 53 B 54 B 55A 56 A 57 B 58 B 59 B 60 B 61 B 62 B 63 B 64 A 65 B 66 B 67 A 68 B 69 B70 B 71 B 72 A 73 B 74 A 75 A 76 B 77 A 78 B 79 B 80 B 81 B 82 A 83 B 84B 85 B 86 B 87 B 88 A 89 A 90 A 91 B 92 A 93 B 94 B 95 B 96 B 97 A 98 B99 B 100 B 101 A 102 A 103 A 104 A 105 B 106 B 107 B 108 A 109 B 110 A111 A 112 B 113 B 114 B 115 A 116 A 117 B 118 B 119 B 120 A 121 B 122 B123 B 124 B 125 B 126 B 127 A 128 B 129 A 130 A 131 A 132 A 133 B 134 B135 A 136 B 137 B 138 B 139 B 140 B 141 B 142 B 143 B 144 A 145 A 146 B147 A 148 A 149 A 150 A 151 B 152 A 153 A 154 A 155 A 156 A 157 B 158 B159 B 160 B 161 B 162 B 163 B 164 B 165 B 166 B 167 B 168 B 169 A 170 A171 B 172 B 173 B 174 B 175 A 176 A 177 A 178 A 179 A 180 A 181 B 182 A183 A 184 B 185 A 186 B 187 A 188 A 189 B 190 A 191 B 192 A 193 A 194 B195 B 196 A 197 A 198 B 199 B 200 B 201 B 202 A 203 A 204 B 205 B 206 A207 B 208 B 209 B 210 A 211 A 212 A 213 B 214 B 215 B 216 B 217 B 218 A219 B 220 A 221 A 222 A 223 A 224 A 225 A 226 A 227 A 228 A 229 A 230 A231 A 232 B 233 A 234 A 235 A 236 A 237 A 238 A 239 B 240 B 241 B 242 A243 A 244 A 245 A 246 A 247 B 248 B 249 A 250 B 251 A 252 A 253 A 254 A255 B 256 B 257 A 258 B 259 A 260 A 261 B 262 B 263 A 264 B 265 A 266 A267 A 268 A 269 A 270 A 271 A 272 A 273 B 274 A 275 A 276 A 277 A 278 A279 A 280 A 281 A 282 B 283 A 284 A 285 A 286 A 287 A 288 B 289 B 290 A291 A 292 B 293 A 294 B 295 B 296 A 297 A 298 A 299 A 300 A 301 A 302 A303 A 304 A 305 B 306 A 307 B 308 A 309 A 310 A 311 A 312 A 313 A 314 A315 A 316 A 317 A 318 A 319 A 320 A 321 B 322 A 323 A 324 A 325 B 326 A327 A 328 A 329 A 330 A 331 A 332 A 333 A 334 A 335 A 336 A 337 A 338 A339 A 340 B 341 A 342 A 343 B 344 A 345 B 346 A 347 A 348 A 349 A 350 A351 A 352 A 353 B 354 B 355 B 356 B 357 A 358 A 359 A 360 A 361 A 362 A363 A 364 A 365 A 366 A 367 A 368 B 369 A 370 A 371 A 372 A 373 B 374 B375 B 376 A 377 A 378 A 379 A 380 A 381 A 382 A 383 A 384 A 385 A 386 A387 A 388 A 389 B 390 A 391 A 392 B 393 A 394 A 395 A 396 A 397 A 398 A399 A 400 A 401 A 402 A 403 A 404 A 405 A 406 A 407 B 408 B 409 A 410 A411 A 412 A 413 A 414 A 415 A 416 A 417 A 418 A 419 A 420 A 421 A 422 A423 A 424 A 425 A 426 A 427 A 428 A 429 B 430 A 431 B 432 A 433 B 434 A435 A 436 A 437 A 438 A 439 B 440 A 441 A 442 A 443 A 444 A 445 A 446 B447 A 448 A 449 A 450 A 451 A 452 A 453 A 454 A 455 A 456 B 457 A 458 A459 A 460 A 461 A 462 A 463 A 464 A 465 B 466 A 467 N.D. 468 N.D. 469N.D. 470 N.D. 471 B 472 A 473 A 474 A 475 A 476 A 477 A 478 A 479 A 480A 481 A 482 A 483 A 484 A 485 A 486 A 487 A 488 B 489 A 490 A 491 A 492A 493 A 494 B 495 A 496 A 497 A 498 A 499 A 500 A 501 A 502 A 503 B 504A 505 B 506 A 507 A 508 A 509 A 510 A 511 A 512 B 513 A 514 B 515 N.D.516 A 517 A 518 A 519 A 520 A 521 A 522 A 523 A 524 A 525 A 526 A 527 A528 B 529 A 530 A 542 A 543 A 554 A 555 A 556 A 557 A 558 A 559 A 560 A561 A 562 A 563 A 564 A 565 A 566 A 567 B 568 A 569 B 570 B 571 A 572 B573 B 574 A 575 A 576 A 577 A 578 A 579 A 580 A 581 A 582 A 583 A 584 A585 A 586 A 587 B 588 A 589 A 590 B 591 B 592 B 593 A 594 B 595 A 596 A597 A 598 A 599 B 600 A 601 A 602 A 603 B 604 A 605 B 606 A 607 A 608 A609 A 610 B 611 B 612 B 613 A 614 A 615 A 616 A 617 B 618 B 619 A 620N.D. 621 B

Example C Improved In Vitro Stability of Compounds Having Substitutionsat R^(A) or R^(B) in Whole Blood

This Example illustrates that exemplary compounds of the presentinvention comprising substitutions at R^(A) or at least one R^(B)exhibit improved whole blood stability compared to compounds in whichR^(A) and both R^(B) substituents are hydrogen.

Materials: The following reagents were used as received: acetonitrile(HPLC grade, Burdick & Jackson, Madison, WI), phosphate buffered saline(PBS), pH 7.4 (Sigma-Aldrich, Co., St. Louis, MO), water (HPLC grade, JTBaker, Phillipsburg, NJ), DMSO (EM Science, Merck KGaA, Darmstadt,Germany) and isopropanol (IPA, reagent grade, EMD Chemicals, Gibbstown,NJ). Propantheline and esmolol (Sigma-Aldrich) were used as the positivecontrol compounds in the assay. Diazepam (Sigma-Aldrich) was used as aninternal standard for quantitation. Human whole blood was obtained fromBioIVT (Westbury, NY) and was of the male gender. All other reagents andsolvents were of the highest analytical grade supplied by Sigma (St.Louis, MO) and were used as received.

Blood Incubations: The in vitro stability of representative KRas G12Cinhibitor compounds of the present invention in the presence whole bloodwas conducted in the following manner. Esmolol or propantheline, whichare known to undergo ester hydrolysis by esterases in blood and plasma,were used as the positive controls in the assays. A 10 mM stock solutionof propantheline, esmolol, or a compound of the present invention inDMSO was diluted to 500 μM with DMSO. Aliquots of whole blood (600 μL),in triplicate, were placed in the appropriate wells of a polypropylene96-deep well plate (Axygen Scientific, Union City, CA). The blood wasdiluted to 50% using PBS, pH 7.4 (600 μL). The diluted blood waspre-incubated for 15 minutes at 37° C. Each well was dosed with 12 μL ofthe 500 μM DMSO stock simultaneously for a final test concentration of 5μM. The plates were mixed at 600 rpm for 10 seconds on a plate shaker(IKA MTS 2/4 Digital Microtiter Shaker, VWR). Aliquots of 100 μL fromeach well of whole blood were transferred to three separate 96-deep wellplates labeled 0, 60, or 240 minutes. At the end of each designated timepoint, the red blood cells were lysed with 100 μL of water, mixed at 600rpm for one minute, and stopped with 800 μL of acetonitrile containingIS (0.625 μM diazepam). The plates were mixed on the plate shaker at 600rpm for one minute and spun in a centrifuge at 2095×g for 7 minutes atroom temperature using an Allegra benchtop centrifuge (Beckman Coulter,Fullerton, CA). Supernatant (100 μL) was transferred to a shallow96-well plate (Costar) using a liquid sample handling system (Apricot,Perkin-Elmer, Boston, MA). The addition of 100 μL of water was added toeach sample of supernatant for a final volume of 200 μL. The plates weresealed and the contents of each well were analyzed by LC-MS/MS.

Analytical quantitation: The LC-MS/MS system was comprised of an HTS-PALautosampler (Leap Technologies, Carrboro, NC), an HP1200 HPLC (Agilent,Palo Alto, CA), and an API4000 triple quadrupole mass spectrometer (PESciex, a division of Applied Biosystems, Foster City, CA).Chromatographic separation of the analyte and internal standard wasachieved at room temperature using a C18 column (Kinetex®, 30×3.0 mm,2.6 μm particle size, Phenomenex, Torrance, CA) in conjunction withgradient conditions using mobile phases A (aqueous 0.1% formic acid with1% isopropyl alcohol) and B (0.1% formic acid in acetonitrile). Thetotal runtime, including re-equilibration, for a single injection was 2minutes Mass spectrometric detection of the analytes was accomplishedusing the ESI⁺ ionization mode. Ion current was optimized duringinfusion of a stock solution of propantheline, esmolol, or therepresentative test compound. Analyte responses, including the IS weremeasured by multiple reaction monitoring (MRM) of transitions unique toeach compound.

Calculations: Data were acquired and peak areas were calculated for testcompounds and the internal standard using Analyst 1.6.2 software(Sciex). The mean peak area ratios were calculated by averaging the peakarea ratios (n=3) of each test compound and the IS for each sample.

Peak area tables were exported to BioAssay Enterprise (CambridgeSoft,Cambridge, MA), where the average analyte-to-internal standard peak arearatios were used to calculate percent remaining (% REM) and half-life(t_(1/2)). Percent remaining (f) was calculated by determining the ratioof the peak area ratio at each time point to the peak area ratio of thetime-zero samples. The t_(1/2) was determined dividing ln(2) by k_(m).The rate of loss of test compound (k_(m)) was determined by linearregression of −ln(f(t)) versus time. The regression used the form“y=mx”, therefore the model forced an intercept of 100% remaining andassumed that the metabolism followed first order kinetics.

The positive control compounds, propantheline or esmolol, andrepresentative KRas G12C inhibitor compounds of the present inventionwere incubated in the presence of human whole blood at 37° C. over a240-minute incubation period. The half-life of propantheline, esmolol,and each test compound after 240 minutes of incubation at 37° C. isshown in Table 4. Key: A≤200 min; B>200 min-≤1000 min; C>1000 min-≤2000min; and D>2000 min

TABLE 4 In Vitro Stability of Exemplary KRas G12C inhibitors in HumanWhole Blood Example No. Compound Half-life propantheline A 235 D 236 B331 B 359 B 367 C 372 D 478 D 479 D 480 D 481 D 482 D 484 A 485 D 490 A491 A 495 B 498 D 501 A 502 B 504 A 506 C 507 D 509 D 510 C 511 D 512 D513 C 514 D 515 D 516 D 517 C 524 D 552 D 557 D 579 C

Results: As expected, positive control propantheline displayed a shorthalf life of 98 min. In comparison, the half life of exemplary KRas G12Cinhibitor compounds comprising substitutions at R^(A) or R^(B) in humanwhole blood was, in some instances, increased by greater than 3-fold orgreater than 4-fold compared to unsubstituted compounds, e.g., Examples331 and 359, resulting in greatly improved pharmacodynamic andpharmacokinetic properties of these compounds resulting in greater invivo stability and increased bioavailability.

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure as come within known or customary practice within theart to which the invention pertains and as may be applied to theessential features hereinbefore set forth, and as follows in the scopeof the appended claims.

1-36. (canceled)
 37. A compound of Formula II-B:

or a pharmaceutically acceptable salt thereof, where the piperazinylring is optionally substituted with R⁸, R¹ is —C(O)C(R^(A))

C(R^(B))_(p) or —SO₂C(R^(A))

C(R^(B))_(p); R² is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl,alkylaminylalkyl, dialkylaminylalkyl, —Z—NR⁵R¹⁰, heterocyclyl,heterocyclylalkyl, aryl, heteroaryl, or heteroarylalkyl, wherein each ofthe Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, andheteroarylalkyl may be optionally substituted with one or more R⁹; eachZ is C1-C4 alkylene; each R³ is independently C1-C3 alkyl, oxo,haloalkyl, hydroxyl or halogen; L is a bond, —C(O)—, or C1-C3 alkylene;R⁴ is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl,wherein each of the cycloalkyl, heterocyclyl, aryl, aralkyl andheteroaryl may be optionally substituted with one or more R⁶, R⁷ or R⁸;each R⁵ is independently hydrogen or C1-C3 alkyl; R⁶ is cycloalkyl,heterocyclyl, heterocyclylalkyl, aryl, or heteroaryl, wherein each ofthe cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionallysubstituted with one or more R⁷; each R⁷ is independently halogen,hydroxyl, C1-C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano,heteroalkyl, hydroxyalkyl or Q-haloalkyl, wherein Q is O or S; R⁸ isoxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, —C(O)OR⁵,—C(O)N(R⁵)₂, —N(R⁵)₂, wherein the C1-C3 alkyl may be optionallysubstituted with cyano, halogen, —OR⁵, —N(R⁵)₂, or heteroaryl; each R⁹is independently hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano,halogen, C1-C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl,heterocyclyl, heterocyclylalkyl, alkoxy, dialkylaminyl,dialkylamidoalkyl, or dialkylaminylalkyl, wherein the C1-C6 alkyl may beoptionally substituted with cycloalkyl; each R¹⁰ is independentlyhydrogen, acyl, C1-C3 alkyl, heteroalkyl or hydroxyalkyl; R¹¹ ishaloalkyl; R^(A) is absent, hydrogen, deuterium, cyano, halogen, C1-C3alkyl, haloalkyl, heteroalkyl, —C(O)N(R⁵)₂, or hydroxyalkyl; each R^(B)is independently hydrogen, deuterium, cyano, C1-C3 alkyl, hydroxyalkyl,heteroalkyl, C1-C3 alkoxy, halogen, haloalkyl, —ZNR⁵R¹¹, —C(O)N(R⁵)₂,—NHC(O)C1-C3 alkyl, —CH₂NHC(O)C1-C3 alkyl, —CH₂N(CH₃)C(O)C1-C3 alkyl,heteroaryl, heteroarylalkyl, dialkylaminylalkyl, or heterocyclylalkylwherein the heterocyclyl portion is substituted with one or moresubstituents independently selected from halogen, hydroxyl, alkoxy andC1-C3 alkyl, wherein the heteroaryl or the heteroaryl portion of theheteroarylalkyl is optionally substituted with one or more R⁷; or when

is a double bond and p is two, one R^(B) is hydrogen and R^(A) and oneR^(B) and the carbon atoms to which they are attached form a 4-8membered partially saturated cycloalkyl substituted with oxo; m is zeroor an integer between 1 and 2; p is one or two; and wherein, when

is a triple bond then R^(A) is absent, p equals one and R^(B) ishydroxyalkyl, or when

is a double bond then R^(A) is present, R^(B) is present and p equalstwo, wherein when R^(A) is hydrogen or C1-C3 alkyl, at least one R^(B)is deuterium, cyano, halogen, haloalkyl, hydroxyalkyl, heteroalkyl,heteroaryl, heteroarylalkyl, —ZNR⁵R¹¹, —C(O)N(R⁵)₂, —NHC(O)C1-C3 alkyl,—CH₂NHC(O)C1-C3 alkyl, —NHC(O)C1-C3 alkyl or heterocyclylalkyl, whereinthe heterocyclyl portion is substituted with one or more substituentsindependently selected from halogen, hydroxyl, alkoxy and C1-C3 alkyl;or when each R^(B) is hydrogen, then R^(A) is deuterium, cyano, halogen,haloalkyl, —C(O)N(R⁵)₂, hydroxyalkyl or heteroalkyl.
 38. The compound ofclaim 37, wherein R¹ is —C(O)C(R^(A))

C(R^(B))_(p) and

is a double bond and R^(A) is hydrogen, p is two and at least one R^(B)is independently deuterium, cyano, halogen, haloalkyl, hydroxyalkyl,heteroalkyl, heteroaryl, heteroarylalkyl, —ZNR⁵R¹¹, —C(O)N(R⁵)₂,—NHC(O)C1-C3 alkyl or heterocyclylalkyl wherein the heterocyclyl portionis substituted with one or more substituents independently selected fromhalogen, hydroxyl, alkoxy and C1-C3 alkyl.
 39. The compound of claim 37,wherein R¹ is —C(O)C(R^(A))

C(R^(B))_(p) and

is a double bond, each R^(B) is hydrogen, and R^(A) is deuterium, cyano,halogen, C1-C3 alkyl, haloalkyl, heteroalkyl, —C(O)N(R⁵)₂, orhydroxyalkyl.
 40. The compound of claim 37, wherein R² isheterocyclylalkyl optionally substituted with one or more R⁹.
 41. Thecompound of claim 40, wherein the heterocyclyl portion of theheterocyclylalkyl is pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, 1,4-oxazepanyl, thiomorpholinyl-1,1-dioxide,3-azabicyclo[3.1.0]hexanyl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, orazabicyclo[2.2.1]heptan-2-yl, each optionally substituted with one ormore R⁹.
 42. The compound of claim 41, wherein each R⁹ is independentlyacyl, oxo, halogen, cyano, C1-C6 alkyl, hydroxyalkyl, heteroalkyl,cycloalkyl, aralkyl or dialkylamidoalkyl.
 43. The compound of claim 42,wherein each R⁹ is independently C1-C6 alkyl, heteroalkyl, or halogen.44. The compound of claim 40, wherein the heterocyclyl portion of theheterocyclylalkyl is pyrrolidinyl optionally substituted with one ormore R⁹.
 45. The compound of claim 37, wherein L is a bond and R⁴ isaryl or heteroaryl, each optionally substituted with one or more R⁶, R⁷or R⁸.
 46. The compound of claim 45, wherein the aryl or heteroaryl aresubstituted with one or more R⁷ independently selected from hydroxyl,amino, halogen, C1-C3 alkyl, haloalkyl, Q-haloalkyl, cycloalkyl andalkoxy.
 47. The compound of claim 45, wherein R⁴ is aryl optionallysubstituted with one or more R⁶ or R⁷.
 48. The compound of claim 47,wherein R⁴ is phenyl or naphthyl, each optionally substituted with oneor more R⁶ or R⁷.
 49. The compound of claim 48, wherein R⁴ is optionallysubstituted with one or more R⁷ independently selected from halogen,C1-C6 alkyl, and haloalkyl.
 50. The compound of claim 37, wherein m iszero.
 51. A pharmaceutically acceptable salt of a compound selected fromthe group consisting of:


52. A compound of the following structure:

or a pharmaceutically acceptable salt thereof.
 53. A pharmaceuticallyacceptable salt of a compound having the following structure:


54. A pharmaceutical composition, comprising a therapeutically effectiveamount of the compound of claim 37, and a pharmaceutically acceptableexcipient.
 55. A method for inhibiting KRas G12C activity in a cell,comprising contacting the cell in which inhibition of KRas G12C activityis desired with an effective amount of the compound of claim
 37. 56. Amethod for treating a cancer comprising administering to a patienthaving cancer a therapeutically effective amount of the compound ofclaim 37, alone or combined with a pharmaceutically acceptable carrier,excipient or diluents, wherein the cancer is selected from the groupconsisting of Cardiac: sarcoma (angiosarcoma, fibrosarcoma,rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma andteratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiatedsmall cell, undifferentiated large cell, adenocarcinoma), alveolar(bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma,chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors,Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma),large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma,Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra(squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma,embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma,interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma,hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;Biliary tract: gall bladder carcinoma, ampullary carcinoma,cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma),fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing'ssarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma,malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginousexostoses), benign chondroma, chondroblastoma, chondromyxofibroma,osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma,hemangioma, granuloma, xanthoma, osteitis deformans), meninges(meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastomamultiform, oligodendroglioma, schwannoma, retinoblastoma, congenitaltumors), spinal cord neurofibroma, meningioma, glioma, sarcoma);Gynecological: uterus (endometrial carcinoma (serous cystadenocarcinoma,mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecalcell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignantteratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma),fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acuteand chronic), acute lymphoblastic leukemia, chronic lymphocyticleukemia, myeloproliferative diseases, multiple myeloma, myelodysplasticsyndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignantlymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cellcarcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma,dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma.57. The method of claim 56, wherein the therapeutically effective amountof the compound is between about 0.01 to 100 mg/kg per day.
 58. Themethod of claim 57, wherein the therapeutically effective amount of thecompound is between about 0.1 to 50 mg/kg per day.
 59. The method ofclaim 56, wherein the cancer wherein the cancer is a KRasG12C-associated cancer.
 60. The method of claim 56, wherein the canceris non-small cell lung cancer.
 61. The method of claim 56, wherein thecancer is colorectal cancer.
 62. The method of claim 56, wherein thecancer is endometrial cancer.
 63. The method of claim 56, wherein thecancer is pancreatic cancer.
 64. A method for treating non-small celllung cancer comprising administering to a patient having non-small celllung cancer a therapeutically effective amount of a compound ofstructure

or a pharmaceutically acceptable salt thereof, alone or combined with apharmaceutically acceptable carrier, excipient or diluents.
 65. A methodfor treating colorectal cancer comprising administering to a patienthaving colorectal cancer a therapeutically effective amount of acompound of structure

or a pharmaceutically acceptable salt thereof, alone or combined with apharmaceutically acceptable carrier, excipient or diluents.
 66. A methodfor treating endometrial cancer comprising administering to a patienthaving endometrial cancer a therapeutically effective amount of acompound of structure

or a pharmaceutically acceptable salt thereof, alone or combined with apharmaceutically acceptable carrier, excipient or diluents.
 67. A methodfor treating pancreatic cancer comprising administering to a patienthaving pancreatic cancer a therapeutically effective amount of acompound of structure

or a pharmaceutically acceptable salt thereof, alone or combined with apharmaceutically acceptable carrier, excipient or diluents.
 68. A methodfor treating ovarian cancer comprising administering to a patient havingovarian cancer a therapeutically effective amount of a compound ofstructure

or a pharmaceutically acceptable salt thereof, alone or combined with apharmaceutically acceptable carrier, excipient or diluents.